AU2022342994A1 - Composition for preventing or treating inflammatory bowel disease containing novel compound - Google Patents
Composition for preventing or treating inflammatory bowel disease containing novel compound Download PDFInfo
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- AU2022342994A1 AU2022342994A1 AU2022342994A AU2022342994A AU2022342994A1 AU 2022342994 A1 AU2022342994 A1 AU 2022342994A1 AU 2022342994 A AU2022342994 A AU 2022342994A AU 2022342994 A AU2022342994 A AU 2022342994A AU 2022342994 A1 AU2022342994 A1 AU 2022342994A1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LTHCSWBWNVGEFE-UHFFFAOYSA-N octanamide Chemical compound CCCCCCCC(N)=O LTHCSWBWNVGEFE-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
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- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
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- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
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- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
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- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
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- 235000012141 vanillin Nutrition 0.000 description 1
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- 229960002675 xylitol Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
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- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Polymers & Plastics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Peptides Or Proteins (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
Abstract
A compound according to the present invention or a pharmaceutically acceptable salt thereof selectively and specifically acts as an agonist for GPR39, promotes the proliferation of intestinal tissue cells and enterohepatic association, promotes cell differentiation, and alleviates inflammation in inflamed intestinal tissue. Thus, the compound can be used in a composition for alleviating and mitigating, preventing, or treating inflammatory bowel disease.
Description
Description
Title of Invention COMPOSITION FOR PREVENTING OR TREATING INFLAMMATORY BOWEL DISEASE CONTAINING NOVEL COMPOUND
Technical Field The present invention relates to a novel compound and a composition for preventing or treating inflammatory bowel disease, comprising the same as an active ingredient.
Background Art About 880 G protein coupled receptors (GPCRs), which are the most abundant membrane proteins in all mammals, are currently known. Of these, about 60% are related to the senses of sight, smell, taste, and the like, and the remaining about 400 GPCRs, including orphan GPCRs, are regulated by various ligands (e.g., proteins, peptide hormones, amino acids, amines and lipids) in the body and are involved in various biological phenomena. In particular, GPCRs are associated with diseases such as metabolic diseases, cardiovascular diseases, degenerative diseases and carcinogenesis. Therefore, it is an important drug target for new drug development, and more than 50% of the drugs developed to date are directly or indirectly related to the activity of GPCR. On the other hand, GPR39 (G protein coupled receptor 39) is one of the orphan GPCRs, for which an intrinsic ligand has not been discovered to date. GPR39 belongs to the Ghrelin receptor (GHSR, growth hormone secretagogue receptor) family, and is known to be distributed in the stomach, intestine, pancreas, liver, kidney, reproductive and adipose tissues (Cell. Mol. Life Sci. 2011, 68:85-95). GPR39, also known as a zinc sensing receptor, is mainly expressed in gastrointestinal tract tissues and is known to promote gastric emptying and enhance secretion of gastric juice through studies on GPR39 deficient mice (Gastroenterology, 2006, 131:1131-1141). In addition, it is known that GPR39 promotes the expression of factors for tight junction in a model of ulcerative colitis, one of inflammatory bowel diseases (IBD) (Phil. Trans. R. Soc. B., 2016, 371:20150420). The above results suggest that GPR39 plays an important role in the function of the gastrointestinal tract in the body, and a modulator for GPR39 is expected to be a new drug candidate for the treatment of inflammatory bowel disease.
Detailed Description of Invention Technical Problem
The present inventors have completed the present invention by confirming that a peptide consisting of a specific amino acid sequence or a variant thereof effectively regulates the activity of GPR39 to activate intestinal function and exhibit anti-inflammatory action. Therefore, an object of the present invention is to provide a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
[Formula 1] R3
N R2y A H 0 0 HH R10' N N N N 9 H O (CH 2 )n H 0 R
HNR R R4 R
Solution to Problem In order to achieve the above object, in one aspect of the present invention, there is provided a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof:
[Formula 1] RR3 N
A i 0 0 Rj N N Ny N 9 H 0, (CH 2 ), H 0 R5
in Formula1I A is -C(-Ro)-, -N= or N-i, Cy is C6- 14 aryl or 5 to 6-membered heteroaryl, R 1 and R3 are each independently hydrogen, Ra, an amine protecting group, C1-6 alkyl substituted with 1 to 3 Ra, C3-10 cycloalkyl, or 5 to 6-membered heterocyclyl, wherein said heterocyclyl has or does not have 1 to 3 substituents selected from phenylethyl and cyclohexylethyl, R2 is hydrogen, Ra, or 5 to 6-membered heterocyclyl, and Ro is hydrogen, or Ro and R2 are linked to each other to form a benzene ring together with the two carbon atoms to which they are attached,
Ra is each independently C3-10 cycloalkyl or C6. 14 aryl, wherein said aryl has or does not have one or more substituents selected from the group consisting of halogen, -OH, C6- 14 aryl substituted with 5 to 6-membered heteroaryl, C 1-6alkyl and C 1-6alkoxy, n is I to 10, R4 is hydrogen, C-i oalkyl or C1-C2 alkylcarbonyl, R 5 is hydrogen, halogen, CF3 or C 1-6alkyl, R 6 is hydrogen, Ci-io alkyl or -S(=0) 20H, R7 and Rs are each independently hydrogen, halogen, nitro, amine or C 1-6alkyl, R9 is -OH or -NH 2, and Rio is hydrogen, an amine protecting group or biotin, wherein said heterocyclyl and heteroaryl each independently contain at least one heteroatom selected from the group consisting of N, S and 0. In another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating inflammatory bowel disease, comprising the compound or pharmaceutically acceptable salt thereof as an active ingredient. In another aspect of the present invention, there is provided a health functional food composition for preventing or mitigating inflammatory bowel disease, comprising the compound or pharmaceutically acceptable salt thereof as an active ingredient.
Effects of Invention A compound according to the present invention or a pharmaceutically acceptable salt thereof selectively and specifically acts as an agonist for GPR39, promotes the proliferation of intestinal tissue cells and tight junction, promotes cell differentiation, and alleviates inflammation in inflamed intestinal tissue. Thus, the compound can be utilized in a composition for alleviating and mitigating, preventing, or treating inflammatory bowel disease.
Brief Description of Drawings Fig. 1 illustrates the results obtained by confirming the purity of HKFY-1 prepared according to one embodiment of the present invention through HPLC. Fig. 2 illustrates the results obtained by confirming the purity of HKFY-2 prepared according to one embodiment of the present invention through HPLC. Fig. 3 illustrates the results obtained by confirming the purity of HKFY-3 prepared according to one embodiment of the present invention through HPLC. Fig. 4 illustrates the results obtained by confirming the purity of HKFY-4 prepared according to one embodiment of the present invention through HPLC. Fig. 5 illustrates the results obtained by confirming the purity of HKFY-5 prepared according to one embodiment of the present invention through HPLC.
Fig. 6 illustrates the results obtained by confirming the purity of HKFY-6 prepared according to one embodiment of the present invention through HPLC. Fig. 7 illustrates the results obtained by confirming the purity of HKFY-7 prepared according to one embodiment of the present invention through HPLC. Fig. 8 illustrates the results obtained by confirming the purity of HKFY-8 prepared according to one embodiment of the present invention through HPLC. Fig. 9 illustrates the results obtained by confirming the purity of HKFY-9 prepared according to one embodiment of the present invention through HPLC. Fig. 10 illustrates the results obtained by confirming the purity of HKFY-10 prepared according to one embodiment of the present invention through HPLC. Fig. 11 illustrates the results obtained by confirming the purity of HKFY-11 prepared according to one embodiment of the present invention through HPLC. Fig. 12 illustrates the results obtained by confirming the purity of HKFY-12 prepared according to one embodiment of the present invention through HPLC. Fig. 13 illustrates the results obtained by confirming the purity of HKFY-13 prepared according to one embodiment of the present invention through HPLC. Fig. 14 illustrates the results obtained by confirming the purity of HKFY-14 prepared according to one embodiment of the present invention through HPLC. Fig. 15 illustrates the results obtained by confirming the purity of HKFY-15 prepared according to one embodiment of the present invention through HPLC. Fig. 16 illustrates the results obtained by confirming the purity of HKFY-16 prepared according to one embodiment of the present invention through HPLC. Fig. 17 illustrates the results obtained by confirming the purity of HKFY-17 prepared according to one embodiment of the present invention through HPLC. Fig. 18 illustrates the results obtained by confirming the purity of HKFY-18 prepared according to one embodiment of the present invention through HPLC. Fig. 19 illustrates the results obtained by confirming the purity of HKFY-19 prepared according to one embodiment of the present invention through HPLC. Fig. 20 illustrates the results obtained by confirming the purity of HKFY-20 prepared according to one embodiment of the present invention through HPLC. Fig. 21 illustrates the results obtained by confirming the purity of HKFY-21 prepared according to one embodiment of the present invention through HPLC. Fig. 22 illustrates the results obtained by confirming the purity of HKFY-22 prepared according to one embodiment of the present invention through HPLC. Fig. 23 illustrates the results obtained by confirming the purity of HKFY-23 prepared according to one embodiment of the present invention through HPLC. Fig. 24 illustrates the results obtained by confirming the purity of HKFY-24 prepared according to one embodiment of the present invention through HPLC.
Fig. 25 illustrates the results obtained by confirming the purity of HKFY-25 prepared according to one embodiment of the present invention through HPLC. Fig. 26 illustrates the results obtained by confirming the purity of HKFY-26 prepared according to one embodiment of the present invention through HPLC. Fig. 27 illustrates the results obtained by confirming the purity of HKFY-27 prepared according to one embodiment of the present invention through HPLC. Fig. 28 illustrates the results obtained by confirming the purity of HKFY-28 prepared according to one embodiment of the present invention through HPLC. Fig. 29 illustrates the results obtained by confirming the purity of HKFY-29 prepared according to one embodiment of the present invention through HPLC. Fig. 30 illustrates the results obtained by confirming the purity of HKFY-30 prepared according to one embodiment of the present invention through HPLC. Fig. 31 illustrates the results obtained by confirming the purity of HKFY-31 prepared according to one embodiment of the present invention through HPLC. Fig. 32 illustrates the results obtained by confirming the purity of HKFY-32 prepared according to one embodiment of the present invention through HPLC. Fig. 33 illustrates the results obtained by confirming the purity of HKFY-33 prepared according to one embodiment of the present invention through HPLC. Fig. 34 illustrates the results obtained by confirming the purity of HKFY-34 prepared according to one embodiment of the present invention through HPLC. Fig. 35 illustrates the results obtained by confirming the purity of HKFY-35 prepared according to one embodiment of the present invention through HPLC. Fig. 36 illustrates the results obtained by confirming the purity of HKFY-36 prepared according to one embodiment of the present invention through HPLC. Fig. 37 illustrates the results obtained by confirming the molecular weight of HKFY 1 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 38 illustrates the results obtained by confirming the molecular weight of HKFY 2 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 39 illustrates the results obtained by confirming the molecular weight of HKFY 3 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 40 illustrates the results obtained by confirming the molecular weight of HKFY 4 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 41 illustrates the results obtained by confirming the molecular weight of HKFY prepared according to one embodiment of the present invention through Ion-Mass. Fig. 42 illustrates the results obtained by confirming the molecular weight of HKFY 6 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 43 illustrates the results obtained by confirming the molecular weight of HKFY 7 prepared according to one embodiment of the present invention through Ion-Mass.
Fig. 44 illustrates the results obtained by confirming the molecular weight of HKFY 8 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 45 illustrates the results obtained by confirming the molecular weight of HKFY 9 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 46 illustrates the results obtained by confirming the molecular weight of HKFY prepared according to one embodiment of the present invention through Ion-Mass. Fig. 47 illustrates the results obtained by confirming the molecular weight of HKFY 11 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 48 illustrates the results obtained by confirming the molecular weight of HKFY 12 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 49 illustrates the results obtained by confirming the molecular weight of HKFY 13 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 50 illustrates the results obtained by confirming the molecular weight of HKFY 14 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 51 illustrates the results obtained by confirming the molecular weight of HKFY prepared according to one embodiment of the present invention through Ion-Mass. Fig. 52 illustrates the results obtained by confirming the molecular weight of HKFY 16 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 53 illustrates the results obtained by confirming the molecular weight of HKFY 17 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 54 illustrates the results obtained by confirming the molecular weight of HKFY 18 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 55 illustrates the results obtained by confirming the molecular weight of HKFY 19 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 56 illustrates the results obtained by confirming the molecular weight of HKFY prepared according to one embodiment of the present invention through Ion-Mass. Fig. 57 illustrates the results obtained by confirming the molecular weight of HKFY 21 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 58 illustrates the results obtained by confirming the molecular weight of HKFY 22 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 59 illustrates the results obtained by confirming the molecular weight of HKFY 23 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 60 illustrates the results obtained by confirming the molecular weight of HKFY 24 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 61 illustrates the results obtained by confirming the molecular weight of HKFY prepared according to one embodiment of the present invention through Ion-Mass. Fig. 62 illustrates the results obtained by confirming the molecular weight of HKFY 26 prepared according to one embodiment of the present invention through Ion-Mass.
Fig. 63 illustrates the results obtained by confirming the molecular weight of HKFY 27 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 64 illustrates the results obtained by confirming the molecular weight of HKFY 28 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 65 illustrates the results obtained by confirming the molecular weight of HKFY 29 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 66 illustrates the results obtained by confirming the molecular weight of HKFY prepared according to one embodiment of the present invention through Ion-Mass. Fig. 67 illustrates the results obtained by confirming the molecular weight of HKFY 31 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 68 illustrates the results obtained by confirming the molecular weight of HKFY 32 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 69 illustrates the results obtained by confirming the molecular weight of HKFY 33 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 70 illustrates the results obtained by confirming the molecular weight of HKFY 34 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 71 illustrates the results obtained by confirming the molecular weight of HKFY prepared according to one embodiment of the present invention through Ion-Mass. Fig. 72 illustrates the results obtained by confirming the molecular weight of HKFY 36 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 73 illustrates the results obtained by analyzing the specific binding of HKFY-34 to the GPR39 receptor using a luciferase assay system (top) and a calcium influx assay system (bottom). Fig. 74 illustrates the results obtained by analyzing the binding capacity of each intrinsic ligand for NTSR1, NTSR2, GHSR, MTLR, NMUR1, NMUR2 and TRHR belonging to the GHSR family and HKFY-34, a HKFY derivative, using a luciferase assay system. Fig. 75 is a graph showing the results obtained by measuring the cell proliferation according to treatment with HKFY-34 at different concentrations in HT-29 cells, an intestinal epithelial cell line. Fig. 76 is a graph showing the results obtained by measuring the calcium concentration in the cells according to treatment with HKFY-34 (10 M) in HT-29 cells, an intestinal epithelial cell line, through Fluo-8 staining. Fig. 77 is a graph showing the results obtained by confirming the mRNA expression levels of occludin and ZO-1 according to treatment with HKFY-34 at different concentrations in HT-29 cells, an intestinal epithelial cell line, through quantitative RT-PCR. *p represents a significant difference (*p <0.05 and ***p<0.001) in the group treated with HKFY-34 relative to the untreated group (vehicle).
Fig. 78 is a graph and diagram showing the results obtained by confirming the protein expression levels of occludin and ZO-1 according to treatment with HKFY-34 at different concentrations in HT-29 cells, an intestinal epithelial cell line, through Western blot. *p represents a significant difference (*p<0.05) in the group treated with HKFY-34 relative to the untreated group (vehicle). Fig. 79 is a graph and diagram showing the results obtained by confirming the phosphorylation of AMPK according to treatment with HKFY-34 at different concentrations in HT-29 cells, an intestinal epithelial cell line, through Western blot. *p represents a significant difference (***p<0.001) in the group treated with HKFY-34 relative to the untreated group (vehicle). Fig. 80 is a graph and diagram showing the results obtained by confirming the phosphorylation of AMPK according to treatment with HKFY-34 after pretreatment with an AMPK inhibitor (STO-609, 1 M), in HT-29 cells, an intestinal epithelial cell line, through Western blot. *p represents a significant difference (***p<0.001) in the group treated with HKFY-34 relative to the group treated with STO-609 alone, and###p represents a significant difference (###p<0.001) in the group treated with the combination of HKFY-34 and STO-609 relative to the group treated with STO-609 alone. Fig. 81 is a graph showing the results obtained by confirming the expression levels of pro-inflammatory cytokines (interleukin (IL)-1 , IL-6, IL-8 and TNF-a) associated with ulcerative colitis according to treatment with HKFY-34 at different concentrations through quantitative RT-PCR, after inflammation was induced with 1 g/mL LPS (lipopolysaccharide) in HT-29 cells, an intestinal epithelial cell line. *p represents a significant difference (*p<0.05 and ***p<0.001) relative to the untreated group (vehicle), and #p represents a significant difference ("p<0.05 and ###p<0.001) relative to the group treated with LPS alone. Fig. 82 is a graph showing the results obtained by confirming the extracellular secretion levels of pro-inflammatory cytokines (IL- I, IL-6, IL-8 and TNF-a) associated with ulcerative colitis according to treatment with HKFY-34 at different concentrations through ELISA (enzymatic immunosorbent assay), after inflammation was induced with 1 g/mL LPS in HT-29 cells, an intestinal epithelial cell line. *p represents a significant difference (***p<0.001) relative to the untreated group (vehicle), and 4p represents a significant difference ("p<0.05, ##p<0.01 and ###p<0.001) relative to the group treated with LPS alone. Fig. 83 is a graph showing the results obtained by measuring the change in body weight during (left) and after (right) intraperitoneal administration of HKFY-34 at doses of 0.1, 1 and 10 mg/kg for 5 days to model mice in which ulcerative colitis was induced by DSS intake (left: daily cumulative body weight loss (%), right: final body weight loss (%)). *p represents a significant difference (***p<0.001) relative to the control group (vehicle), and 4p represents a significant difference (4p<0.05 and 44p<0.01) relative to the negative control group (treated with DSS alone). Fig. 84 is a graph and diagram showing the results obtained by measuring the length of the colon in model mice in which ulcerative colitis was induced by DSS after intraperitoneal administration of HKFY-34 at doses of 0.1, 1 and 10 mg/kg for 5 days to model mice in which ulcerative colitis was induced by DSS intake. *p represents a significant difference (***p<0.001) relative to the control group (vehicle), and 4p represents a significant difference (###p<0.001) relative to the negative control group (treated with DSS alone). Fig. 85 is a graph showing the degree of the stool consistency (diarrhea) as a score by observing stool during intraperitoneal administration of HKFY-34 at doses of 0.1, 1 and 10 mg/kg to model mice in which ulcerative colitis was induced by DSS intake. *p represents a significant difference (***p<0.001) relative to the control group (vehicle), and 4p represents a significant difference (4p<0.05) relative to the negative control group (treated with DSS alone). Fig. 86 is a graph showing the degree of blood in stool as a score by observing stool during intraperitoneal administration of HKFY-34 at doses of 0.1, 1 and 10 mg/kg to model mice in which ulcerative colitis was induced by DSS intake. *p represents a significant difference (***p<0.001) relative to the control group (vehicle), and 4p represents a significant difference ("p<0.05) relative to the negative control group (treated with DSS alone). Fig. 87 is a graph showing the results obtained by confirming the mRNA expression levels of IL- I, IL-6, IL-8 and TNF-a in the colon tissue of model mice in which ulcerative colitis was induced by DSS through quantitative RT-PCR, after intraperitoneal administration of HKFY-34 at doses of 0.1, 1 and 10 mg/kg for 5 days to model mice in which ulcerative colitis was induced by DSS intake. *p represents a significant difference (*p<0.05, **p<0.01 and ***p<0.001) relative to the control group (vehicle), and 4p represents a significant difference ("p<0.05, ##p<0.01 and ###p<0.001) relative to the negative control group (treated with DSS alone). Fig. 88 is a graph showing the results obtained by confirming the concentration of IL- Iand TNF-a in the blood of model mice in which ulcerative colitis was induced by DSS through ELISA, after intraperitoneal administration of HKFY-34 at doses of 0.1, 1 and 10 mg/kg for 5 days to model mice in which ulcerative colitis was induced by DSS intake. *p represents a significant difference (*p<0.05, **p<0.01 and ***p<0.001) relative to the control group (vehicle), and 4p represents a significant difference (p<0.01 and """p<0.001) relative to the negative control group (treated with DSS alone). Fig. 89 is a graph and diagram showing the results (left) obtained by H&E staining of the colon tissue of model mice in which ulcerative colitis was induced by DSS and the results (right) obtained by analyzing and quantifying the degree of inflammatory damage (macrophage infiltration rate, mucus secreting cell loss rate, villus structural collapse rate and secreting gland loss rate) compared to the control group, after intraperitoneal administration of HKFY-34 at doses of 0.1, 1 and 10 mg/kg for 5 days to model mice in which ulcerative colitis was induced by DSS intake. #p represents a significant difference (#p<0.01 and ###p<0.001) relative to the negative control group (treated with DSS alone). Fig. 90 is a graph showing the results obtained by confirming the mRNA expression levels of occludin and ZO-1 in the colon tissue of model mice in which colitis was induced by DSS through quantitative RT-PCR, after intraperitoneal administration of HKFY-34 at doses of 0.1, 1 and 10 mg/kg for 5 days to model mice in which ulcerative colitis was induced by DSS intake. *p represents a significant difference (*p<0.05, **p<0.01 and ***p<0.001) relative to the control group (vehicle), and "p represents a significant difference (p<0.01 and ###p<0.001) relative to the negative control group (treated with DSS alone). Fig. 91 is a graph showing the results obtained by measuring the change in body weight during (left) and after (right) intraperitoneal administration of HKFY-34 at a dose of mg/kg to wild type and GPR39 genetically deficient (Gpr39 -/-) model mice in which ulcerative colitis was induced by DSS intake (left: daily cumulative body weight loss (%), right: final body weight loss (%)). *p represents a significant difference (**p<0.01 and ***p<0.001) relative to the control group (vehicle), and "p represents a significant difference (#p<0.01) relative to the negative control group (treated with DSS alone). Fig. 92 is a graph and diagram showing the results obtained by measuring the length of the colon in model mice in which ulcerative colitis was induced by DSS after intraperitoneal administration of HKFY-34 at a dose of 10 mg/kg for 5 days to wild type and GPR39 genetically deficient (Gpr39 -/-) model mice in which ulcerative colitis was induced by DSS intake. *p represents a significant difference (***p<0.001) relative to the control group (vehicle), and "p represents a significant difference (#p<0.01) relative to the negative control group (treated with DSS alone). Fig. 93 is a graph showing the degree of the stool consistency (diarrhea) as a score by observing stool during intraperitoneal administration of HKFY-34 at a dose of 10 mg/kg to wild type and GPR39 genetically deficient (Gpr39 -/-) model mice in which ulcerative colitis was induced by DSS intake. #p represents a significant difference (p<0.05) relative to the negative control group (treated with DSS alone). Fig. 94 is a graph showing the degree of blood in stool as a score by observing stool during intraperitoneal administration of HKFY-34 at a dose of 10 mg/kg to wild type and GPR39 genetically deficient (Gpr39 -/-) model mice in which ulcerative colitis was induced by DSS intake. Fig. 95 is a graph and diagram showing the results (left) obtained by H&E staining of the colon tissue of model mice in which ulcerative colitis was induced by DSS and the results (right) obtained by analyzing and quantifying the degree of inflammatory damage (macrophage infiltration rate, mucus secreting cell loss rate, villus structural collapse rate and secreting gland loss rate) compared to the control group, after intraperitoneal administration of HKFY-34 at a dose of 10 mg/kg for 5 days to wild type and GPR39 genetically (Gpr39-) deficient model mice in which ulcerative colitis was induced by DSS intake. Fig. 96 illustrates the results obtained by confirming 1 H NMR of HKFY-1 prepared according to one embodiment of the present invention. Fig. 97 illustrates the results obtained by confirming 1 H NMR of HKFY-2 prepared according to one embodiment of the present invention. Fig. 98 illustrates the results obtained by confirming 1 H NMR of HKFY-34 prepared according to one embodiment of the present invention. Fig. 99 illustrates the results obtained by confirming the purity of HKFY-37 prepared according to one embodiment of the present invention through HPLC. Fig. 100 illustrates the results obtained by confirming the molecular weight of HKFY-37 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 101 illustrates the results obtained by confirming the purity of HKFY-38 prepared according to one embodiment of the present invention through HPLC. Fig. 102 illustrates the results obtained by confirming the molecular weight of HKFY-38 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 103 illustrates the results obtained by confirming the purity of HKFY-39 prepared according to one embodiment of the present invention through HPLC. Fig. 104 illustrates the results obtained by confirming the molecular weight of HKFY-39 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 105 illustrates the results obtained by confirming the purity of HKFY-40 prepared according to one embodiment of the present invention through HPLC. Fig. 106 illustrates the results obtained by confirming the molecular weight of HKFY-40 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 107 illustrates the results obtained by confirming the purity of HKFY-41 prepared according to one embodiment of the present invention through HPLC. Fig. 108 illustrates the results obtained by confirming the molecular weight of HKFY-41 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 109 illustrates the results obtained by confirming the purity of HKFY-42 prepared according to one embodiment of the present invention through HPLC. Fig. 110 illustrates the results obtained by confirming the molecular weight of HKFY-42 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 111 illustrates the results obtained by confirming the purity of HKFY-43 prepared according to one embodiment of the present invention through HPLC. Fig. 112 illustrates the results obtained by confirming the molecular weight of HKFY-43 prepared according to one embodiment of the present invention through Ion-Mass.
Fig. 113 illustrates the results obtained by confirming the purity of HKFY-44 prepared according to one embodiment of the present invention through HPLC. Fig. 114 illustrates the results obtained by confirming the molecular weight of HKFY-44 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 115 illustrates the results obtained by confirming the purity of HKFY-45 prepared according to one embodiment of the present invention through HPLC. Fig. 116 illustrates the results obtained by confirming the molecular weight of HKFY-45 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 117 illustrates the results obtained by confirming the purity of HKFY-46 prepared according to one embodiment of the present invention through HPLC. Fig. 118 illustrates the results obtained by confirming the molecular weight of HKFY-46 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 119 illustrates the results obtained by confirming the purity of HKFY-47 prepared according to one embodiment of the present invention through HPLC. Fig. 120 illustrates the results obtained by confirming the molecular weight of HKFY-47 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 121 illustrates the results obtained by confirming the purity of HKFY-48 prepared according to one embodiment of the present invention through HPLC. Fig. 122 illustrates the results obtained by confirming the molecular weight of HKFY-48 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 123 illustrates the results obtained by confirming the purity of HKFY-49 prepared according to one embodiment of the present invention through HPLC. Fig. 124 illustrates the results obtained by confirming the molecular weight of HKFY-49 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 125 illustrates the results obtained by confirming the purity of HKFY-50 prepared according to one embodiment of the present invention through HPLC. Fig. 126 illustrates the results obtained by confirming the molecular weight of HKFY-50 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 127 illustrates the results obtained by confirming the purity of HKFY-51 prepared according to one embodiment of the present invention through HPLC. Fig. 128 illustrates the results obtained by confirming the molecular weight of HKFY-51 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 129 illustrates the results obtained by confirming the purity of HKFY-52 prepared according to one embodiment of the present invention through HPLC. Fig. 130 illustrates the results obtained by confirming the molecular weight of HKFY-52 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 131 illustrates the results obtained by confirming the purity of HKFY-53 prepared according to one embodiment of the present invention through HPLC.
Fig. 132 illustrates the results obtained by confirming the molecular weight of HKFY-53 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 133 illustrates the results obtained by confirming the purity of HKFY-54 prepared according to one embodiment of the present invention through HPLC. Fig. 134 illustrates the results obtained by confirming the molecular weight of HKFY-54 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 135 illustrates the results obtained by confirming the purity of HKFY-55 prepared according to one embodiment of the present invention through HPLC. Fig. 136 illustrates the results obtained by confirming the molecular weight of HKFY-55 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 137 illustrates the results obtained by confirming the purity of HKFY-56 prepared according to one embodiment of the present invention through HPLC. Fig. 138 illustrates the results obtained by confirming the molecular weight of HKFY-56 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 139 illustrates the results obtained by confirming the purity of HKFY-57 prepared according to one embodiment of the present invention through HPLC. Fig. 140 illustrates the results obtained by confirming the molecular weight of HKFY-57 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 141 illustrates the results obtained by confirming the purity of HKFY-58 prepared according to one embodiment of the present invention through HPLC. Fig. 142 illustrates the results obtained by confirming the molecular weight of HKFY-58 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 143 illustrates the results obtained by confirming the purity of HKFY-59 prepared according to one embodiment of the present invention through HPLC. Fig. 144 illustrates the results obtained by confirming the molecular weight of HKFY-59 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 145 illustrates the results obtained by confirming the purity of HKFY-60 prepared according to one embodiment of the present invention through HPLC. Fig. 146 illustrates the results obtained by confirming the molecular weight of HKFY-60 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 147 illustrates the results obtained by confirming the purity of HKFY-61 prepared according to one embodiment of the present invention through HPLC. Fig. 148 illustrates the results obtained by confirming the molecular weight of HKFY-61 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 149 illustrates the results obtained by confirming the purity of HKFY-62 prepared according to one embodiment of the present invention through HPLC. Fig. 150 illustrates the results obtained by confirming the molecular weight of HKFY-62 prepared according to one embodiment of the present invention through Ion-Mass.
Fig. 151 illustrates the results obtained by confirming the purity of HKFY-63 prepared according to one embodiment of the present invention through HPLC. Fig. 152 illustrates the results obtained by confirming the molecular weight of HKFY-63 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 153 illustrates the results obtained by confirming the purity of HKFY-64 prepared according to one embodiment of the present invention through HPLC. Fig. 154 illustrates the results obtained by confirming the molecular weight of HKFY-64 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 155 illustrates the results obtained by confirming the purity of HKFY-65 prepared according to one embodiment of the present invention through HPLC. Fig. 156 illustrates the results obtained by confirming the molecular weight of HKFY-65 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 157 illustrates the results obtained by confirming the purity of HKFY-66 prepared according to one embodiment of the present invention through HPLC. Fig. 158 illustrates the results obtained by confirming the molecular weight of HKFY-66 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 159 illustrates the results obtained by confirming the purity of HKFY-67 prepared according to one embodiment of the present invention through HPLC. Fig. 160 illustrates the results obtained by confirming the molecular weight of HKFY-67 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 161 illustrates the results obtained by confirming the purity of HKFY-68 prepared according to one embodiment of the present invention through HPLC. Fig. 162 illustrates the results obtained by confirming the molecular weight of HKFY-68 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 163 illustrates the results obtained by confirming the purity of HKFY-69 prepared according to one embodiment of the present invention through HPLC. Fig. 164 illustrates the results obtained by confirming the molecular weight of HKFY-69 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 165 illustrates the results obtained by confirming the purity of HKFY-70 prepared according to one embodiment of the present invention through HPLC. Fig. 166 illustrates the results obtained by confirming the molecular weight of HKFY-70 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 167 illustrates the results obtained by confirming the purity of HKFY-71 prepared according to one embodiment of the present invention through HPLC. Fig. 168 illustrates the results obtained by confirming the molecular weight of HKFY-71 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 169 illustrates the results obtained by confirming the purity of HKFY-72 prepared according to one embodiment of the present invention through HPLC.
Fig. 170 illustrates the results obtained by confirming the molecular weight of HKFY-72 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 171 illustrates the results obtained by confirming the purity of HKFY-73 prepared according to one embodiment of the present invention through HPLC. Fig. 172 illustrates the results obtained by confirming the molecular weight of HKFY-73 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 173 illustrates the results obtained by confirming the purity of HKFY-74 prepared according to one embodiment of the present invention through HPLC. Fig. 174 illustrates the results obtained by confirming the molecular weight of HKFY-74 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 175 illustrates the results obtained by confirming the purity of HKFY-75 prepared according to one embodiment of the present invention through HPLC. Fig. 176 illustrates the results obtained by confirming the molecular weight of HKFY-75 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 177 illustrates the results obtained by confirming the purity of HKFY-76 prepared according to one embodiment of the present invention through HPLC. Fig. 178 illustrates the results obtained by confirming the molecular weight of HKFY-76 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 179 illustrates the results obtained by confirming the purity of HKFY-77 prepared according to one embodiment of the present invention through HPLC. Fig. 180 illustrates the results obtained by confirming the molecular weight of HKFY-77 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 181 illustrates the results obtained by confirming the purity of HKFY-78 prepared according to one embodiment of the present invention through HPLC. Fig. 182 illustrates the results obtained by confirming the molecular weight of HKFY-78 prepared according to one embodiment of the present invention through Ion-Mass. Fig. 183 illustrates the results obtained by confirming the purity of HKFY-79 prepared according to one embodiment of the present invention through HPLC. Fig. 184 illustrates the results obtained by confirming the molecular weight of HKFY-79 prepared according to one embodiment of the present invention through Ion-Mass.
Best Mode for Carrying out the Invention Hereinafter, the present invention will be described in more detail. In one aspect of the present invention, there is provided a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
[Formula 1]
R3R R5 N
A 00 H H Rls N N N N R H H R R 0 (CH 2 )nH 0
HN R7 / 0" in Formula 1 A is -C(-Ro)-, -N= or -N(-R1)-, Cy is C6-14aryl or 5 to 6-membered heteroaryl, R 1 and R3 are each independently hydrogen, Ra, an amine protecting group, C 1-6 alkyl substituted with 1 to 3 Ra, C3.10 cycloalkyl, or 5 to 6-membered heterocyclyl, wherein said heterocyclyl has or does not have 1 to 3 substituents selected from phenylethyl and cyclohexylethyl, R2 is hydrogen, Ra, or 5 to 6-membered heterocyclyl, and Ro is hydrogen, or Ro and R2 are linked to each other to form a benzene ring together with the two carbon atoms to which they are attached, Ra is each independently C 3-10 cycloalkyl or C6.14 aryl, wherein said aryl has or does not have one or more substituents selected from the group consisting of halogen, -OH, C 6-14 aryl substituted with 5 to 6-membered heteroaryl, C 1-6 alkyl and C 1.6 alkoxy, n is 1 to 10, R 4 is hydrogen, Ci1io alkyl or C1-C2 alkylarbonyl, R5 is hydrogen, halogen, CF3 or C 1-6 alkyl, R6 is hydrogen, Ciio alkyl or -S(=0) 20H, R7 and R8 are each independently hydrogen, halogen, nitro, amine or C1-6 alkyl, R9 is -OH or -NH 2, and Rio is hydrogen, an amine protecting group or biotin, wherein said heterocyclyl and heteroaryl each independently contain at least one heteroatom selected from the group consisting of N, S and 0. In one embodiment of the present invention, the compound may be a peptide, and the peptide may be a derivative of a peptide having a sequence of four amino acids, and the sequence of four amino acids may be His-Lys-Phe-Tyr (SEQ ID NO: 1).
In accordance with the conventional use in the art, in the Formula herein, is used to denote a bond that is the point of attachment of a moiety or substituent to a core or skeletal structure.
As used herein, the term "alkyl" is a hydrocarbon having primary, secondary, tertiary or cyclic carbon atoms. For example, an alkyl group may have 1 to 20 carbon atoms (i.e., C1 C 2 0 alkyl), 1 to 10 carbon atoms (i.e., CI-C10 alkyl), or 1 to 6 carbon atoms (i.e., C1 -C alkyl). Examples of suitable alkyl groups include methyl (Me, -CH 3), ethyl (Et, -CH 2CH 3), 1-propyl (n-Pr, n-propyl, -CH 2CH 2CH 3), 2-propyl (i-Pr, i-propyl, -CH(CH 3) 2 ), 1-butyl (n-Bu, n-butyl, CH 2CH2 CH2CH 3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2CH(CH 3) 2), 2-butyl (s-Bu, s-butyl, -CH(CH 3)CH 2 CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, CH 2CH2 CH2CH 2CH3), 2-pentyl (-CH(CH 3)CH 2CH2 CH3), 3-pentyl (-CH(CH 2 CH3) 2), 2 methyl-2-butyl (-C(CH 3) 2CH 2CH3), 3-methyl-2-butyl (-CH(CH 3)CH(CH 3) 2), 3-methyl-I butyl (-CH 2 CH2 CH(CH3 ) 2), 2-methyl-I-butyl (-CH 2 CH(CH 3)CH 2 CH3), 1-hexyl( CH 2CH2 CH2CH 2CH2 CH3), 2-hexyl (-CH(CH 3)CH 2CH2 CH2CH 3), 3-hexyl ( CH(CH 2 CH3)(CH 2CH 2CH3)), 2-methyl-2-pentyl (-C(CH 3) 2 CH2CH 2CH3), 3-methyl-2-pentyl (-CH(CH 3)CH(CH 3)CH 2 CH3), 4-methyl-2-pentyl (-CH(CH 3)CH 2 CH(CH 3) 2), 3-methyl-3 pentyl (-C(CH 3)(CH 2 CH3) 2), 2-methyl-3-pentyl (-CH(CH 2CH 3)CH(CH 3) 2),2,3-dimethyl-2 butyl (-C(CH 3) 2 CH(CH 3) 2), 3,3-dimethyl-2-butyl (-CH(CH 3)C(CH 3) 3 , and octyl( (CH 2) 7CH3 ), but are not limited thereto. As used herein, the term "cycloalkyl" refers to a saturated monocycle or poly-cycle containing only carbon atoms in the ring. A cycloalkyl may have 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicyclic cycloalkyl, and up to about 20 carbon atoms as a poly-cycle. A monocyclic cycloalkyl has 3 to 6 ring atoms, and more typically 5 or 6 ring atoms. A bicyclic cycloalkyl has 7 to 12 ring atoms arranged in a bicyclo [4,5], [5,5], [5,6] or
[6,6] system, or 9 to 10 ring atoms arranged in a bicyclo [5,6] or [6,6] system or a spiro-fused ring. Non-limiting examples of monocyclic cycloalkyls may include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (each of which may be substituted or unsubstituted). As used herein, the term "heterocyclyl" includes the radicals of heterocycles described in the literature [Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), specifically Chapters 1, 3, 4, 6, 7 and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, from 1950 to present), specifically Volumes 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960) 82:5566], but is not limited thereto. The term "heterocyclyl" refers to an aromatic or non aromatic ring radical that is formed as saturated or unsaturated single or multiple rings and has one or more heteroatoms. For example, "5 to 6-membered heterocyclyl" may refer to a heterocyclyl having a total of 5 to 6 heteroatoms and/or carbon atoms. As used herein, when "heterocyclyl" is described as a substituent, it can be used as a term encompassing "heterocycloalkyl" and "heteroaryl." Herein, "heterocycloalkyl" refers to a saturated ring radical that is formed as single or multiple rings and has one or more heteroatoms, and "heteroaryl" refers to an aromatic ring radical that is formed as single or multiple rings and has one or more heteroatoms, and "heteroatom" may be selected from N, 0 and S. Non limiting examples of heteroaryl rings include all those listed in the definition of "heterocyclyl," including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl (which may be substituted or unsubstituted), and the like. As used herein, the term "heteroaryl" refers to an aromatic heterocyclyl having one or more heteroatoms in the ring. Non-limiting examples of suitable heteroatoms that may be included in the aromatic ring include oxygen, sulfur and nitrogen. Non-limiting examples of heteroaryl rings include all those listed in the definition of "heterocyclyl," including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl (which may be substituted or unsubstituted), and the like. As used herein, the term "alkoxy" refers to a group having the Formula -0-alkyl, in which an alkyl group as defined above is attached to a parent compound through an oxygen atom. The alkyl portion of the alkoxy group may have 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C1 2 alkoxy), or 1 to 6 carbon atoms (i.e., Ci-C6 alkoxy). Examples of suitable alkoxy groups include methoxy (-O-CH 3 or -OMe), ethoxy( OCH 2 CH3 or -OEt), t-butoxy (-O-C(CH 3 )3 or -O-tBu), and the like, but are not limited thereto. As used herein, the term "alkylcarbonyl" refers to a group having the Formula C(=O)-alkyl, in which an alkyl group as defined above is attached to a parent compound through a carbon atom. The alkyl portion of the alkylcarbonyl group may have 1 to 20 carbon atoms (i.e., C1-C2o alkylcarbonyl) or 5 to 17 carbon atoms (i.e., C-C1 7 alkylcarbonyl). Examples of suitable alkylcarbonyl groups include caprylic (-C(=)(CH 2 )6 CH3), capric( C(=O)(CH 2 ) 8 CH3 ), lauric (-C(=O)(CH 2) 1 oCH 3), myristic (-C(=O)(CH 2) 12 CH3), palmitic( C(=O)(CH 2) 14 CH3), and the like, but are not limited thereto. The term "substituted" with respect to alkyl, aryl, heteroaryl, heterocyclyl, carbocyclyl (for example, cycloalkyl), and the like, for example, "substituted alkyl", "substituted aryl", "substituted heteroaryl", "substituted heterocyclyl" and "substituted carbocyclyl (for example, substituted cycloalkyl)" refer to alkyl, aryl, heteroaryl, heterocyclyl, carbocyclyl (for example, cycloalkyl) in which one or more hydrogen atoms are each independently substituted with a non-hydrogen substituent. Typical substituents include -X, -R, -0-, =0, -OR, -SR, -S-, -NR 2, -N+R3 , =NR, -C(X) 3, -CN, -OCN, -SCN, -N=C=O, NCS, -NO, -NO 2 , =N-OH, =N 2 , -N3 , -NHC(=O)R, -C(=O)R, -C(=O)NRR -S(=0) 2 0-, S(=0) 2 0H, -S(=0)2 R, -OS(=0) 2 0R, -S(=0) 2 NR, -S(=O)R, -OP (=O)(OR) 2, -C(=O)R, alkylene-C(=)R, -C(S)R, -C(=O)OR, alkylene-C(=)OR, -C(=0)O-, alkylene-C(=O)O-, C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, alkylene-C(=O)NRR, -C(=S)NRR, -C(
NR)NRR (wherein, each X is independently halogen: F, Cl, Br, or I, and R is independently H, alkyl, aryl, arylalkyl or heterocycle), but are not limited thereto. Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. In addition, the present invention includes pharmaceutically acceptable salts and addition salts of the compounds of the present invention, such as hydrochloride, hydrobromide or trifluoroacetate addition salts and sodium, potassium and magnesium salts, but is not limited thereto. It will be appreciated by one of ordinary skill in the art that when a moiety such as "alkyl", "aryl", "heterocyclyl," etc. is substituted by one or more substituents, it may optionally be referred to as a moiety such as "alkylene", "arylene", "heterocyclylene" (i.e., meaning that one or more hydrogen atoms of the parent "alkyl", "aryl", "heterocyclyl" moiety are substituted with the substituents as stated above). When a moiety such as "alkyl","aryl", "heterocyclyl," etc. is referred to herein as "substituted" or shown as substituted in the drawings (or optionally substituted, for example, when the number of substituents is from 0 to a positive number), the terms "alkyl", "aryl", "heterocyclyl" and the like should be understood as interchangeable with "alkylene", "arylene", "heterocyclylene" and the like. It will be appreciated by one of ordinary skill in the art that the substituents and other moieties of the compound of Formula 1 should be selected to provide a compound that is sufficiently stable to provide a pharmaceutically useful compound that can be formulated into an acceptably stable pharmaceutical composition. The compound of Formula 1 having such stability is considered to be included in the scope of the present invention. As used herein, the term "optionally substituted" refers to a particular moiety of a compound of Formula 1 having one, two, or more substituents. In the present invention, the compound represented by Formula 1 may be an optical isomer of an L-form or a D-form. In the compound represented by Formula 1 according to the present invention, A may
be -C(-Ro)- or -N(-Ri)-, and Ri may be hydrogen, or , but is not limited thereto. In addition, Ro may be hydrogen, and R 2 may be hydrogen,
or , or Ro and R2 may be linked to each other to form a benzene ring together with the two carbon atoms to which they are attached, but is not limited thereto. In addition, R3 may be one selected from the group consisting of and ,and preferably, it may be but is not limited thereto. In addition, n may be 3 or 4, R4 may be heptylcarbonyl, R5 may be methyl or CF3, R6 may be hydrogen or S(=0)2OH, and R7 and R8 may be each independently hydrogen or amine. In addition, R7 and R8 may be each independently hydrogen, R9 may be -OH, and Rio may be hydrogen, p-toluenesulfonyl (p-Ts), t-butoxycarbonyl (t-Boc) or biotin, but is not limited thereto. In addition, Rs, R7 and R8 are not particularly limited at positions to be substituted on the benzene ring. For example, R5 may be substituted at an ortho (o-), meta (m-) or para (p-) position. It may be any one selected from the group consisting of: 1) His(trt)-Lys(caprylic)-Phe-Tyr, 2) Biotin-His(trt)-Lys(caprylic)-Phe-Tyr, 3) His(benzyl)-Lys(caprylic)-Phe-Tyr, 4) d-His(trt)-Lys(caprylic)-Phe-Tyr, 5) His(4-methyltrityl)-Lys(caprylic)-Phe-Tyr, 6) His(DAMP-3)-Lys(caprylic)-Phe-Tyr, 7) His(DAMP-5)-Lys(caprylic)-Phe-Tyr, 8) His(DAMP-2)-Lys(caprylic)-Phe-Tyr, 9) His(2-phenylethyl)-Lys(caprylic)-Phe-Tyr, 10) His(2-naphthalen-I -ethyl)-Lys(caprylic)-Phe-Tyr, 11) His(2-cyclohexylethyl)-Lys(caprylic)-Phe-Tyr,
12) His(trt)-Lys(caprylic)-d-Phe-Tyr, 13) His(trt)-Lys(caprylic)-d-Phe(4-Cl)-Tyr, 14) d-His(trt)-Lys(caprylic)-d-Phe(4-Cl)-d-Tyr, ) His(trt)-Lys(caprylic)-d-Phe(4-Cl)-d-Tyr, 16) His(trt)-d-Lys(caprylic)-d-Phe(4-Cl)-Tyr, 17) His(3,3-diphenylpropyl)-Lys(caprylic)-Phe-Tyr, 18) His(Fm)-Lys(caprylic)-Phe-Tyr, 19) His(phenylpropyl)-Lys(caprylic)-Phe-Tyr, ) His(4-methoxylbenzhydryl)-Lys(caprylic)-Phe-Tyr, 21) His(4-chlorobenzhydryl)-Lys(caprylic)-Phe-Tyr, 22) His(4-methylbenzhydryl)-Lys(caprylic)-Phe-Tyr, 23) His(admantanmethyl)-Lys(caprylic)-Phe-Tyr, 24) His(trt)-Lys(capric)-Phe-Tyr, ) His(trt)-Lys(lauric)-Phe-Tyr, 26) His(trt)-Lys(myristic)-Phe-Tyr, 27) His(trt)-Lys(palmitic)-Phe-Tyr, 28) His(trt)-Lys(caprylic)-d-Phe(F)-Tyr, 29) His(trt)-Lys(caprylic)-d-Phe(Br)-Tyr, ) His(trt)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 31) d-His(trt)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 32) His(1,3-difluorobenzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 33) His(benzhydryl)-Lys(caprylic)-Phe-Tyr, 34) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, ) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(SO3H), 36) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(2,6-di-methyl), 57) His(2-phenyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 58) His(1-phenyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 59) His(1,2-diphenyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, ) His(2-(4-tert-butyl)phenyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 61) His(1-(4-tert-butyl)phenyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 62) d-His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 63) His(thiophene)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 64) His(4-methoxybenzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, and ) His(4-hydroxybenzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr 66) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr-NH2 67) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3-chloro) 68) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3-nitro) 69) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3,5-nitro)
70) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3-amino) 71) His(benzhydryl)-Orn(caprylic)-d-Phe(4-methyl)-Tyr 72) Biotin-His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr 73) His(trt)-Lys(caprylic)-d-3Pal-Tyr 74) His(trt)-Lys(caprylic)-d-2Nal-Tyr 75) His(tosyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr 76) His(trt)-Lys(caprylic)-d-Phe(4-CF3)-Tyr 77) His(tbm)-Lys(caprylic)-d-Phe(4-CF3)-Tyr 78) Boc-Trp-Lys(caprylic)-d-Phe(4-methyl)-Tyr and 79) His(benzhydryl)Lys(caprylic). In the present invention, the compound may be (Xi)-(X2)-[His(trt)-Lys(caprylic) Phe-Tyr], wherein Xi and X 2 may be each independently any one amino acid selected from amino acids or derivatives thereof, and specifically, it may be 37) Gly-Ser-His(trt) Lys(caprylic)-Phe-Tyr (SEQ ID NO: 2). In the compound represented by Formula 1 according to the present invention, 1 to amino acids or derivatives thereof may be further bound to the C terminus of the compound. Specifically, the compound may be [His(trt)-Lys(caprylic)-Phe-Tyr]-(X3)a-(X4) (X5)c-(X6)d-(X7)e-(X8)f-(X9)g, wherein X3 to X 9may be each independently any one amino acid selected from 20 amino acids or derivatives thereof, and a to g may be 0 or 1, and at least one of them may be 1. More specifically, the compound may be any one selected from the group consisting of 38) His(trt)-Lys(caprylic)-Phe-Tyr-Ser-Asp-Gln-Gln-Ala-Arg-Phe (SEQ ID NO: 3), 39) His(trt)-Lys(caprylic)-Phe-Tyr-Ser-Gln-Asn-Gly-Ala-Arg-Phe (SEQ ID NO: 4), 40) His(trt)-Lys(caprylic)-Phe-Tyr-Ser-His-Gln-Gln-Ala-Arg-Phe (SEQ ID NO: 5), 41) His(trt)-Lys(caprylic)-Phe-Tyr-Gln-Asn-Gly-Ala-Arg-Phe (SEQ ID NO: 6), 42) His(trt) Lys(caprylic)-Phe-Tyr-His-Gln-Gln-Ala-Arg-Phe (SEQ ID NO: 7), 43) His(trt)-Lys(caprylic) Phe-Tyr-Gln-Asn-Gln-Ala-Arg-Phe (SEQ ID NO: 8), and 44) His(trt)-Lys(caprylic)-Phe-Tyr Trp (SEQ ID NO: 9). In another aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt thereof, wherein the compound consists of [His(trt) Lys(caprylic)]-(Xi)h-(X11)i, wherein Xio and Xi imay be each independently any one amino acid selected from 20 amino acids or derivatives thereof, and h and i may be 0 or 1, and at least one of them may be 1. Specifically, the compound may be any one selected from the group consisting of 45) Biotin-His(trt)-Lys(caprylic)-Bip-Tyr (SEQ ID NO: 10), 46) His(trt) Lys(caprylic)-Phe-Trp (SEQ ID NO: 11), 47) His(trt)-Lys(caprylic)-Tyr-Phe (SEQ ID NO: 12), 48) His(trt)-Lys(caprylic)-Tyr-Tyr (SEQ ID NO: 13), 49) His(trt)-Lys(caprylic)-Phe, 50) His(trt)-Lys(caprylic)-Phe-Ser (SEQ ID NO: 14), and 51) His(trt)-Lys(caprylic)-Leu-Tyr (SEQ ID NO: 15).
In another aspect of the present invention, there is provided any one selected from the group consisting of 52) His(trt)-Phe-Tyr-Asp-Gln-Gln-Ala-Arg-Phe (SEQ ID NO: 16), 53) His(trt)-Gly-Ser-Lys(caprylic)-Phe-Tyr (SEQ ID NO: 17), 54) Lys(caprylic)-Phe-Tyr, 55) Lys(caprylic)-His(trt)-Phe-Tyr (SEQ ID NO: 18), 56) His(trt)-Lys(caproic)-Phe-Tyr-Asp-Gln Gln-Ala-Arg-Phe (SEQ ID NO: 19) and 79) His(benzhydryl)Lys(caprylic). In the present invention, the compound may be present in a mixture of L-form and D form amino acids (for example, which may be any one amino acid selected from the group consisting of His, Lys, Phe, Tyr, Ser, Asp, Gln, Ala, Arg and Asn, but is not limited thereto), where "d" means a D-form amino acid. In the present invention, "trt" is triphenylmethyl, "Boc" is t-butyloxycarbonyl, "tBu" is t-butyl, "Fmoc" is 9-fluorenylmethyloxycarbonyl, "dde" is 1-(4,4-dimethyl-2,6 dioxocyclohexylidene)ethyl, and "Bip" is biphenylalanine. In the present invention, the "biotin" is a kind of vitamin B complex required for the growth of animals and plants. The natural one is a D-form isomer, in which the bond of the two pentagonal rings is in the cis configuration. The other seven isomers, such as L-biotin in cis form or allobiotin in trans form, do not exhibit coenzyme activity. In the present invention, the "amine protecting group" may be a protecting group selected from the group consisting of t-butyloxycarbonyl (Boc), p-toluenesulfonyl (Ts), fluorenylmethyloxycarbonyl, benzyl, triphenylmethyl and carboxybenzyl, and it may be preferably p-toluenesulfonyl or t-butyloxycarbonyl. In the present invention, when Rio in the compound represented by Formula 1 is biotin, the biotin may be a compound represented by Formula 2 below.
[Formula 2] H S HN
C o," N H HH 2~ j
In Formula 2, n may be 1 to 10, and it may be preferably 4, but is not limited thereto. In addition, the compound represented by Formula 1 according to the present invention may be represented by Formula 3 below, when A is -N=, R2 is hydrogen, R3 is
-.I. , n is 4, R4 is heptylcarbonyl, Cy is phenyl, R5 is methyl, R 6 is S(=0) 20H, R7 ,
R8 and Rio are each independently hydrogen, and R9 is -OH, and the amino acid of SEQ ID NO: 1 may be a substituted form, such as His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl) Tyr. The IUPAC name of the compound represented by Formula 3 below is ((R)-2-((S)-2 ((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3
(p-tolyl)propanoyl)-L-tyrosine, and in one embodiment of the present invention, it was named HKFY-34.
[Formula 3] 4
In one embodiment of the present invention, it was confirmed that the peptide derivative, which is a compound having the structure of Formula 1 according to the present invention, selectively and specifically binds to GPR39 (G protein coupled receptor 39), one of the orphan G protein coupled receptors (orphan GPCR), which is a membrane protein (Tables 3 to 5 and Figs. 73 and 74). In another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating inflammatory bowel disease, comprising the compound or pharmaceutically acceptable salt thereof as an active ingredient. As used herein, the term "inflammation" is a response to protect a living body against harmful factors, and includes a series of processes involving immune cells, blood vessels, and inflammatory mediators to inhibit cell damage, remove damaged tissue and necrotic cells, and regenerate tissue. As used herein, the term "inflammatory bowel disease (IBD)" refers to a disease that causes chronic inflammation in the gastrointestinal tract, and may include both infectious enteritis such as bacterial, viral, amebic, and tuberculous enteritis, and inflammatory diseases occurring in all intestines, such as ischemic bowel disease and radiation enteritis. Although the cause of inflammatory bowel disease has not been clearly identified, it is known to be affected by genetic and environmental influences and mediated by immunological abnormalities. The inflammatory bowel disease may be Crohn's disease, ulcerative colitis, intestinal Behcet's disease and enteritis, but is not limited thereto. The "Crohn's disease" is a chronic inflammatory bowel disease that affects the entire gastrointestinal tract from the oral cavity to the anus. It is an autoimmune disease, most of which occurs in the ileocaecal region, which is the border between the small intestine and the large intestine, and occurs frequently in the large intestine, terminal ileum, and small intestine. Crohn's disease is characterized by repeated symptomatic and asymptomatic phases showing symptoms such as abdominal pain and diarrhea. The cause of the disease is not clear, but it is assumed that mycobacterial infection, measles virus infection, and an excessive immune response to normal bacteria in the digestive tract are involved. "Ulcerative colitis" is a kind of diffuse nonspecific inflammation disease that mainly invades mucous membranes and forms rotting or ulcers. The cause of ulcerative colitis is not clearly identified, and it causes various systemic symptoms such as bloody diarrhea. "Behcet's disease" is a disease in which oral and genital ulcers and ocular inflammation appear repeatedly, and is a systemic and chronic disease that affects the cardiovascular system, nervous system, digestive tract, liver, spleen, kidney and lung. When Behcet's disease affects the intestinal tract, it is called "intestinal Behcet's disease". Intestinal Behcet's disease is a nonspecific, recurrent chronic inflammatory disease, which is accompanied by symptoms such as abdominal pain and diarrhea, and may be accompanied by complications such as bleeding and perforation. In one embodiment of the present invention, when HT-29 cells were treated with the peptide derivative according to the present invention, cell proliferation and binding were enhanced (Figs. 75 to 78). In addition, it alleviated inflammation in a cell model of inflammatory bowel disease (IBD) (Fig. 81). When an ulcerative colitis mouse model was treated with the peptide derivative according to the present invention, body weight loss and intestine length contraction, which are symptoms ofulcerative colitis, were inhibited, and diarrhea, blood in stool, and inflammatory response in intestinal tissue were alleviated. Therefore, it was confirmed that the therapeutic effect for inflammatory bowel disease was excellent (Figs. 83 to 89). In addition, when GPR39 deficient mice in which ulcerative colitis was induced were treated with the peptide derivative according to the present invention, no significant alleviating effect was observed (Figs. 91 to 95). Therefore, it was confirmed that the peptide derivative according to the present invention acts specifically on GPR39 against inflammatory bowel disease. As used herein, the term "prevention" refers to any action that inhibits or delays the occurrence, spread, and recurrence of a target disease by administration of the composition. As used herein, the term "treatment" refers to any action that improves or beneficially changes the symptoms of a target disease by administration of the composition. Specifically, it includes curing, alleviating, avoiding, preventing, delaying or reducing symptoms caused by inflammatory bowel disease. The pharmaceutical composition may further comprise suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions. In addition, it can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods. Suitable preparations known in the art may be those disclosed in the literature (Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA). In addition, the pharmaceutical composition may comprise carriers, excipients and diluents including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. When formulating the composition, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, which are commonly used. Solid preparations for oral administration of the "pharmaceutical composition" of the present invention may include tablets, pills, powders, granules, capsules, and the like. Such a solid preparation may be prepared by mixing the composition with at least one or more excipients, for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration may include suspensions, internal solutions, emulsions, syrups, and the like, and may comprise, in addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, flavouring agents, and preservatives. Preparations for parenteral administration may include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like may be used. The composition is preferably formulated in a dosage form specific to a particular patient. For each unit dose for oral administration, it is preferable to contain the compound of Formula 1 or a pharmaceutically acceptable salt thereof in an amount of 0.1 mg/kg to 500 mg/kg, 1 mg/kg to 100 mg/kg, or 10 mg/kg to 50 mg/kg. A preferred dosage of the pharmaceutical composition varies depending on the condition and body weight of the patient, the severity of the disease, the type of drug, the route and duration of administration, but can be appropriately selected by one of ordinary skill in the art. A daily administration dose suitable for oral administration is about 0.01 to 40 mg/kg of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, and may be administered 1 to 6 times a day depending on the condition of the patient.
In addition, the pharmaceutical composition may be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the prevention and treatment of inflammatory bowel disease. In another aspect of the present invention, there is provided a method for preventing or treating inflammatory bowel disease, comprising administering the compound or pharmaceutically acceptable salt thereof to a mammal. In this case, the compound or a salt thereof, inflammatory bowel disease, administration, prevention and treatment are the same as described above. In another aspect of the present invention, there is provided the use of the compound or pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating inflammatory bowel disease. In this case, the compound or a salt thereof, inflammatory bowel disease, prevention and treatment are the same as described above. In another aspect of the present invention, there is provided a health functional food composition for preventing or mitigating inflammatory bowel disease, comprising the compound or cytologically acceptable salt thereof as an active ingredient. In this case, the compound or a salt thereof, inflammatory bowel disease and prevention are the same as described above. The health functional food according to the present invention may be in the form of powder, granule, tablet, capsule or beverage, and may be candy, chocolate, gum, tea, vitamin complex, health supplement food, and the like. The health functional food may be prepared in various forms such as tablets, capsules, powders, granules, liquids, pills, and the like in order to obtain useful effects for mitigating inflammatory bowel disease, but is not limited thereto. In this case, the content of the compound or cytologically acceptable salt thereof according to the present invention included in the health functional food may be typically 0.01 to 50 %by weight, or 0.1 to 20 %by weight based on the total food weight. In addition, in the case of the health beverage composition, it may be included in an amount of 0.02 to 10 g, or 0.3 to 1 g, based on 100 mL of the health beverage composition. The food may further comprise a cytologically acceptable food supplementary additive together with the compound or cytologically acceptable salt thereof according to the present invention. The health functional food according to the present invention may comprise additives that are commonly used in food compositions to improve smell, taste, appearance, and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like may be included. In addition, minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), and copper (Cu) may be included. In addition, amino acids such as lysine, tryptophan, cysteine, and valine may be included.
In addition, food additives such as preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), disinfectants (bleaching powder, high bleaching powder, sodium hypochlorite, etc.), antioxidants (butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), etc.), coloring agents (tar color, etc.), color formers (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite), seasonings (MSG sodium glutamate, etc.), sweeteners (dulcin, cyclemate, saccharin, sodium, etc.), flavors (vanillin, lactones, etc.), expanding agents (alum, D-potassium hydrogen tartrate, etc.), strengthening agents, emulsifiers, thickeners, coating agents, gum base agents, foam inhibitors, solvents, and modifiers may be added. The additive may be selected according to the type of food and used in an appropriate amount.
Mode for Carrying out the Invention Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples are only for illustrating the present invention, and the present invention is not limited to the following examples. Example 1. Preparation of HKFY derivatives Example 1.1. Preparation of HKFY-1 In order to prepare His(trt)-Lys(caprylic)-Phe-Tyr (N6-octanoyl-N2-(Nt-trityl-L histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, HKFY-1), Fmoc-Tyr(tBu) and DMF (dimethylformamide) were loaded onto the trityl resin to prepare Fmoc-Tyr(tBu)-trityl resin. DMF containing 20% piperidine and Fmoc-Phe-OH and HOBt (hydroxyl-benzotriazole) were added to Fmoc-Tyr(tBu)-trityl resin to prepare Fmoc-Phe-Tyr(tBu)-trityl resin. DMF containing 2% NH 2NH 2 .H20 was added to Fmoc-Lys(dde)-OH, and dde was removed to prepare Fmoc-Lys-OH. DMF containing caprylic acid and HOBt and DIC was added to the Fmoc-Lys-OH to prepare Fmoc-Lys(caprylic acid)-OH. DMF containing 20% piperidine was added to the Fmoc-Phe-Tyr(tBu)-trityl resin, and HOBt (hydroxyl-benzotriazole) was added to the Fmoc-Lys(caprylic acid)-OH to prepare Fmoc-Lys(caprylic acid)-Phe-Tyr(tBu)-trityl resin. DMF containing 20% piperidine was added to the Fmoc-Lys(caprylic acid)-Phe Tyr(tBu)-trityl resin, and Boc-His(trt)-OH and HOBt (hydroxyl-benzotriazole) were added to prepare Boc-His(trt)-Lys(caprylic acid)-Phe-Tyr(tBu)-trityl resin. The protecting group was cleaved from the Boc-His(trt)-Lys(caprylic acid)-Phe Tyr(tBu)-trityl resin, and the resin was then purified to prepare His(trt)-Lys(caprylic acid) Phe-Tyr. The purity, molecular weight and 'H NMR of the HKFY-1 are shown in Figs. 1, 37 and 96, respectively. Example 1.2. Preparation of HKFY-2
In order to prepare biotin ((S)-3-([1,1'-biphenyl]-4-yl)-2-((S)-6-octanamido-2-((S)-2 (5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3-(1-trityl 1H-imidazol-4-yl)propanamido)hexanamido)propanoyl)-L-tyrosine, DMF containing 20% piperidine was added to the Fmoc-Lys(caprylic acid)-Phe-Tyr(tBu)-trityl resin obtained from Example 1.1., and Fmoc-His(trt)-OH was added to prepare Fmoc-His(trt)-Lys(caprylic acid) Phe-Tyr(tBu)-trityl resin. D-biotin was added to the resin in the same manner to prepare D biotin-His(trt)-Lys(caprylic acid)-Phe-Tyr(tBu)-trityl resin. The protecting group of the resin was cleaved, and the resin was then purified to prepare biotin-His(trt)-Lys(caprylic acid)-Phe-Tyr (N6-octanoyl-N2-(Na-(5-((3aS,4S,6aR)-2 oxohexahydro-1H-thieno[3,4-dlimidazol-4-yl)pentanoyl)-Nt-trityl-L-histidyl)-L-lysyl-L phenylalanyl-L-tyrosine). The purity, molecular weight and 1 H NMR of the HKFY-2 are shown in Figs. 2, 38 and 97, respectively. Example 1.3. Preparation of HKFY-3 His(benzyl)-Lys(caprylic)-Phe-Tyr (N2-(Nt-benzyl-L-histidyl)-N6-octanoyl-L-lysyl L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(benzyl) OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-3 are shown in Figs. 3 and 39, respectively. Example 1.4. Preparation of HKFY-4 d-His(trt)-Lys(caprylic)-Phe-Tyr (N6-octanoyl-N2-(Nt-trityl-D-histidyl)-L-lysyl-L phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-d-His(trt) was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-4 are shown in Figs. 4 and 40, respectively. Example 1.5. Preparation of HKFY-5 His(4-methyltrityl)-Lys(caprylic)-Phe-Tyr (N2-(Nt-(diphenyl (p-tolyl)methyl)-L histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(4-methyltrityl)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-5 are shown in Figs. 5 and 41, respectively. Example 1.6. Preparation of HKFY-6 His(DAMP-3)-Lys(caprylic)-Phe-Tyr (N2-((S)-2-amino-3-(1,3-diphenethyl-2,3 dihydro-1H-imidazol-4-yl)propanoyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(DAMP-3)-OH was used instead of Boc His(trt)-OH obtained during the preparation process of Example 1.1.
The purity and molecular weight of the HKFY-6 are shown in Figs. 6 and 42, respectively. Example 1.7. Preparation of HKFY-7 His(DAMP-5)-Lys(caprylic)-Phe-Tyr (N2-((S)-2-amino-3-(3-(2-cyclohexylethyl) 2,3-dihydro-1H-imidazol-4-yl)propanoyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(DAMP-5)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-7 are shown in Figs. 7 and 43, respectively. Example 1.8. Preparation of HKFY-8 His(DAMP-2)-Lys(caprylic)-Phe-Tyr (N2-((S)-2-amino-3-(1,3-bis(2 cyclohexylethyl)-2,3-dihydro-1H-imidazol-4-yl)propanoyl)-N6-octanoyl-L-lysyl-L phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(DAMP-2) OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-8 are shown in Figs. 8 and 44, respectively. Example 1.9. Preparation of HKFY-9 His(DAMP-2)-Lys(caprylic)-Phe-Tyr (N6-octanoyl-N2-(Nt-phenethyl-L-histidyl)-L lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(2 phenylethyl)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-9 are shown in Figs. 9 and 45, respectively. Example 1.10. Preparation of HKFY-10 His(2-naphthalen-1-ethyl)-Lys(caprylic)-Phe-Tyr (N2-(Nt-(naphthalen-1-ylmethyl) L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(2-naphthalen-1-ethyl)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-10 are shown in Figs. 10 and 46, respectively. Example 1.11. Preparation of HKFY-11 His(2-cyclohexylethyl)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-(2-cyclohexylethyl)-L histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(2-cyclohexylethyl)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-11 are shown in Figs. 11 and 47, respectively.
Example 1.12. Preparation of HKFY-12 In order to prepare His(trt)-Lys(caprylic)-d-Phe-Tyr (N6-decanoyl-N2-(Nt-trityl-L histidyl)-L-lysyl-D-phenylalanyl-L-tyrosine, HKFY-12), Fmoc-Tyr(tBu) and DMF (dimethylformamide) were loaded onto the trityl resin to prepare Fmoc-Tyr(tBu)-trityl resin. DMF containing 20% piperidine and Fmoc-d-Phe-OH of Formula 8 and HOBt (hydroxyl benzotriazole) were added to Fmoc-Tyr(tBu)-trityl resin to prepare Fmoc-d-Phe-Tyr(tBu) trityl resin. Fmoc-Lys(caprylic acid)-OH and HOBt (hydroxyl-benzotriazole) were added to the Fmoc-d-Phe-Tyr(tBu)-trityl resin to prepare Fmoc-Lys(caprylic acid)-d-Phe-Tyr(tBu)-trityl resin. DMF containing 20% piperidine was added to Fmoc-Lys(caprylic acid)-d-Phe Tyr(tBu)-trityl resin, and Boc-His(trt)-OH and HOBt (hydroxyl-benzotriazole) were added to prepare Boc-His(trt)-Lys(caprylic acid)-d-Phe-Tyr(tBu)-trityl resin. The protecting group was cleaved from the Boc-His(trt)-Lys(caprylic acid)-d-Phe Tyr(tBu)-trityl resin, and the resin was then purified to prepare His(trt)-Lys(caprylic)-d-Phe Tyr. The purity and molecular weight of the HKFY-12 are shown in Figs. 12 and 48, respectively. Example 1.13. Preparation of HKFY-13 His(trt)-Lys(caprylic)-d-Phe(4-Cl)-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H imidazol-4-yl)propanamido)-6-(non-1-en-2-ylamino)hexanamido)-3-(4 chloropheny)propanoyl)-L-tyrosine, HKFY-13) was prepared in the same manner except that Fmoc-d-Phe(4-Cl)-OH was used instead of Fmoc-d-Phe-OH obtained during the preparation process of Example 1.6. The purity and molecular weight of the HKFY-13 are shown in Figs. 13 and 49, respectively. Example 1.14. Preparation of HKFY-14 Fmoc-d-Tyr(tBu)-trityl resin was prepared in the same manner except that Fmoc-d Tyr(tBu)-OH was used instead of Fmoc-Tyr(tBu)-OH obtained during the preparation process of Example 1.13. During the subsequent process, Boc-His(trt)-OH was changed to Boc-d His(trt)-OH to prepare d-His(trt)-Lys(caprylic)-d-Phe(4-Cl)-d-Tyr (((R)-2-((S)-2-((R)-2 amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4 chlorophenyl)propanoyl)-D-tyrosine). The purity and molecular weight of the HKFY-14 are shown in Figs. 14 and 50, respectively. Example 1.15. Preparation of HKFY-15 His(trt)-Lys(caprylic)-d-Phe(4-Cl)-d-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-chlorophenyl)propanoyl)-D tyrosine) was prepared in the same manner except that Boc-His(trt)-OH was used instead of Boc-d-His(trt)-OH obtained during the preparation process of Example 1.14. The purity and molecular weight of the HKFY-15 are shown in Figs. 15 and 51, respectively. Example 1.16. Preparation of HKFY-16 His(trt)-d-Lys(caprylic)-d-Phe(4-Cl)-Tyr (((R)-2-((R)-2-((S)-2-amino-3-(1-trityl-1H imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-chlorophenyl)propanoyl)-L tyrosine) was prepared in the same manner as in Example 1.13., except that Fmoc-d Lys(caprylic)-OH was used by replacing Fmoc-Lys(dde)-OH with Fmoc-d-Lys(dde)-OH in the preparation process using Fmoc-Lys(caprylic)-OH instead of Fmoc-Lys(dde)-OH obtained during the preparation process of Example 1.13. The purity and molecular weight of the HKFY-16 are shown in Figs. 16 and 52, respectively. Example 1.17. Preparation of HKFY-17 His(3,3-diphenylpropyl)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-(2,2-diphenylethyl)-L histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(3,3-diphenylpropyl)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-17 are shown in Figs. 17 and 53, respectively. Example 1.18. Preparation of HKFY-18 His(Fm)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-(9H-fluoren-9-yl)-L-histidyl)-N6 octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(Fm)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-18 are shown in Figs. 18 and 54, respectively. Example 1.19. Preparation of HKFY-19 His(phenylpropyl)-Lys(caprylic acid)-Phe-Tyr (N6-octanoyl-N2-(Nt-phenethyl-L histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(phenylpropyl)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-19 are shown in Figs. 19 and 55, respectively. Example 1.20. Preparation of HKFY-20 His(methoxylbenzhydryl)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-((4 methoxyphenyl)(phenyl)methyl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(methoxylbenzhydryl)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-20 are shown in Figs. 20 and 56, respectively. Example 1.21. Preparation of HKFY-21 His(4-chlorobenzhydryl)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-((R)-(4 chlorophenyl)(phenyl)methyl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(4-chlorobenzhydryl)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-21 are shown in Figs. 21 and 57, respectively. Example 1.22. Preparation of HKFY-22 His(methylbenzhydryl)-Lys(caprylic acid)-Phe-Tyr (N6-octanoyl-N2-(Nt-((R) phenyl (p-tolyl)methyl)-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(methylbenzhydryl)-OH was used instead of Boc-His(trt) OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-22 are shown in Figs. 22 and 58, respectively. Example 1.23. Preparation of HKFY-23 His(admantanmethyl)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-(adamantan-1-yl)-L histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(admantanmethyl)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-23 are shown in Figs. 23 and 59, respectively. Example 1.24. Preparation of HKFY-24 His(trt)-Lys(capric)-Phe-Tyr (N6-decanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L phenylalanyl-L-tyrosine, HKFY-24) was prepared in the same manner except that capric acid instead of caprylic acid was added to Fmoc-Lys-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-24 are shown in Figs. 24 and 60, respectively. Example 1.25. Preparation of HKFY-25 His(trt)-Lys(lauric)-Phe-Tyr (N6-dodecanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L phenylalanyl-L-tyrosine, HKFY-25) was prepared in the same manner except that lauric acid instead of caprylic acid was added to Fmoc-Lys-OH obtained during the preparation process of Example 1.1.
The purity and molecular weight of the HKFY-25 are shown in Figs. 25 and 61, respectively. Example 1.26. Preparation of HKFY-26 His(trt)-Lys(myristic)-Phe-Tyr (N6-tetradecanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl L-phenylalanyl-L-tyrosine, HKFY-26) was prepared in the same manner except that myristic acid instead of caprylic acid was added to Fmoc-Lys-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-26 are shown in Figs. 26 and 62, respectively. Example 1.27. Preparation of HKFY-27 His(trt)-Lys(palmitic)-Phe-Tyr (N6-palmitoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L phenylalanyl-L-tyrosine, HKFY-27) was prepared in the same manner except that palmitic acid instead of caprylic acid was added to Fmoc-Lys-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-27 are shown in Figs. 27 and 63, respectively. Example 1.28. Preparation of HKFY-28 His(trt)-Lys(caprylic)-d-Phe(4-F)-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-fluorophenyl)propanoyl)-L tyrosine, HKFY-28) was prepared in the same manner except that Fmoc-d-Phe(4-F)-OH was used instead of Fmoc-d-Phe-OH obtained during the preparation process of Example 1.6. The purity and molecular weight of the HKFY-28 are shown in Figs. 28 and 64, respectively. Example 1.29. Preparation of HKFY-29 His(trt)-Lys(caprylic)-d-Phe(4-Br)-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-bromophenyl)propanoyl)-L tyrosine, HKFY-29) was prepared in the same manner except that Fmoc-d-Phe(4-Br)-OH was used instead of Fmoc-d-Phe-OH obtained during the preparation process of Example 1.6. The purity and molecular weight of the HKFY-29 are shown in Figs. 29 and 65, respectively. Example 1.30. Preparation of HKFY-30 His(trt)-Lys(caprylic)-d-Phe(4-methyl)-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(1-trityl 1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L tyrosine, HKFY-30) was prepared in the same manner except that Fmoc-d-Phe(4-methyl)-OH was used instead of Fmoc-d-Phe-OH obtained during the preparation process of Example 1.6. The purity and molecular weight of the HKFY-30 are shown in Figs. 30 and 66, respectively. Example 1.31. Preparation of HKFY-31
D-His(trt)-Lys(caprylic)-d-Phe(4-methyl)-Tyr ((R)-2-((S)-2-((R)-2-amino-3-(1-trityl 1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L tyrosine) was prepared in the same manner except that Boc-d-His(trt)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.30. The purity and molecular weight of the HKFY-31 are shown in Figs. 31 and 67, respectively. Example 1.32. Preparation of HKFY-32 His(1,3-difluorobenzhydryl)-Lys(caprylic)-d-Phe(methyl)-Tyr (((2R)-2-((2S)-2 ((2S)-2-amino-3-(1-((2,4-difluorophenyl)(phenyl)methyl)-1H-imidazol-4-yl)propanamido)-6 octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Boc-His(1,3-difluorobenzhydryl)-OH was used instead of Boc-His(benzhydryl) OH among the constituent amino acids of Example 1.34. below. The purity and molecular weight of the HKFY-32 are shown in Figs. 32 and 68, respectively. Example 1.33. Preparation of HKFY-33 His(benzhydryl)-Lys(caprylic)-Phe-Tyr (N2-(Nt-benzhydryl-L-histidyl)-N6 octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner except that Boc-His(benzhydryl)-OH was used instead of Boc-His(trt)-OH obtained during the preparation process of Example 1.1. The purity and molecular weight of the HKFY-33 are shown in Figs. 33 and 69, respectively. Example 1.34. Preparation of HKFY-34 In order to prepare His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr (((R)-2-((S) 2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido) 3-(p-tolyl)propanoyl)-L-tyrosine, HKFY-34), Fmoc-Tyr(tBu) and DMF (dimethylformamide) were loaded onto the trityl resin to prepare Fmoc-Tyr(tBu)-trityl resin. DMF containing 20% piperidine and Fmoc-d-Phe(4-methyl)-OH and HOBt (hydroxyl-benzotriazole) were added to Fmoc-Tyr(tBu)-trityl resin to prepare Fmoc-d-Phe(4-methyl)-Tyr(tBu)-trityl resin. DMF containing 2% NH 2NH 2 .H20 was added to Fmoc-Lys(dde)-OH, and dde was removed to prepare Fmoc-Lys-OH. DMF containing caprylic acid, HOBt and DIC was added to the Fmoc-Lys-OH to prepare Fmoc-Lys(caprylic acid)-OH, and Boc-His(trt)-OH was used to prepare Boc-His(benzhydryl)-OH. DMF containing 20% piperidine was added to the Fmoc-d-Phe(4-methyl)-Tyr(tBu) trityl resin, and HOBt (hydroxyl-benzotriazole) was added to the Fmoc-Lys(caprylic acid) OH to prepare Fmoc-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(tBu)-trityl resin. DMF containing 20% piperidine was added to Fmoc-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(tBu) trityl resin, and Boc-His(benzhydryl)-OH and HOBt (hydroxyl-benzotriazole) were added to prepare a peptide of Boc-His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(tBu)-trityl resin. The protecting group was cleaved from the Boc-His(benzhydryl)-Lys(caprylic acid) d-Phe(4-methyl)-Tyr(tBu)-trityl resin, and the resin was then purified to prepare His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr-OH. The purity, molecular weight and 1 H NMR of the HKFY-34 are shown in Figs. 34, 70 and 98, respectively. Example 1.35. Preparation of HKFY-35 His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr ((SO 3 H)-OH (S)-2-((R)-2 ((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6 octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(4-(sulfooxy)phenyl)propanoic acid) was prepared in the same manner except that Fmoc-Tyr(SO3H)-OH was used instead of Fmoc Tyr(tBu)-OH obtained during the preparation process of Example 1.34. The purity and molecular weight of the HKFY-35 are shown in Figs. 35 and 71, respectively. Example 1.36. Preparation of HKFY-36 His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr ((2.6-di-methyl)-OH (S)-2 ((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6 octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(4-hydroxy-2,6 dimethylphenyl)propanoic acid) was prepared in the same manner except that Fmoc-Tyr(2.6 di-methyl)-OH was used instead of Fmoc-Tyr(tBu)-OH obtained during the preparation process of Example 1.34. The purity and molecular weight of the HKFY-36 are shown in Figs. 36 and 72, respectively. Example 1.37. Preparation of HKFY-37 DMF containing 20% piperidine was added to Fmoc-His(trt)-Lys(caprylic)-Phe-Tyr OH-trityl resin obtained during the preparation process of Example 1.1., and HOBt (hydroxyl-benzotriazole) was added to Fmoc-Ser(tBu)-OH to prepare Fmoc-Ser(tBu) His(trt)-Lys(caprylic)-Phe-Tyr-OH-trityl resin. DMF containing 20% piperidine was added to the resin, and HOBt (hydroxyl-benzotriazole) was added to Fmoc-Gly-OH to prepare Fmoc Gly-Ser(tBu)-His(trt)-Lys(caprylic)-Phe-Tyr-OH-trityl resin. The protecting group was cleaved from the Fmoc-Gly-Ser(tBu)-His(trt) Lys(caprylic)-Phe-Tyr-OH-trityl resin, and the resin was then purified to prepare Gly-Ser His(trt)-Lys(caprylic acid)-Phe-Tyr (N2-(Na-glycyl-L-seryl-Nt-trityl-L-histidyl)-N6 octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine). The purity and molecular weight of the HKFY-37 are shown in Figs. 99 and 100, respectively. Example 1.38. Preparation of HKFY-38
In order to prepare HKFY-38 ((3S,6S,9S,12S,15S)-15-((S)-2-amino-3-(1-trityl-1H imidazol-4-yl)propanamido)-12-benzyl-3-(((6S,9S,12S,15S)-1,18-diamino-6-(((S)-1-amino 1-oxo-3-phenylpropan-2-yl)carbamoyl)-12-(3-amino-3-oxopropyl)-1-imino-9-methyl 8,11,14,18-tetraoxo-2,7,10,13-tetraazaoctadecan-15-yl)carbamoyl)-9-(4-hydroxybenzyl)-6 (hydroxymethyl)-5,8,11,14,21-pentaoxo-4,7,10,13,20-pentaazaoctacosanoic acid), Fmoc-Phe OH and DMF (dimethylformamide) were loaded onto the trityl resin to prepare Fmoc-Phe trityl resin. DMF containing 20% piperidine and Fmoc-Arg(pbf)-OH and HOBt (hydroxyl benzotriazole) were added to the Fmoc-Phe-trityl resin to prepare Fmoc-Arg(pbf)-Phe-trityl resin. DMF containing 20% piperidine and Fmoc-Ala-OH and HOBt (hydroxyl benzotriazole) were added to Fmoc-Arg(pbf)-Phe-trityl resin to prepare Fmoc-Ala-Arg(pbf) Phe-trityl resin. Fmoc-Gln(trt)-OH, Fmoc-Gln(trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Ser(tBu) OH, Fmoc-Tyr(tbu)-OH, Fmoc-Phe-OH were sequentially added in the same manner as above to prepare Fmoc-Phe-Tyr(tBu)-Ser(tBu)-Asp(tBu)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe trityl resin. DMF containing 20% piperidine and Fmoc-Lys(caprylic)-OH obtained from Example 1.1. and HOBt (hydroxyl-benzotriazole) were added to the resin to prepare Fmoc Lys(caprylic)-Phe-Tyr(tBu)-Ser(tBu)-Asp(tBu)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin. DMF containing 20% piperidine and Fmoc-His(trt)-OH obtained from Example 1.1. and HOBt (hydroxyl-benzotriazole) were added to the resin to prepare Fmoc-His(trt) Lys(caprylic)-Phe-Tyr (tBu)-Ser(tBu)-Asp(tBu)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trity resin. The protecting group was cleaved from the Fmoc-His(trt)-Lys(caprylic)-Phe-Tyr (tBu)-Ser(tBu)-Asp(tBu)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin, and the resin was then purified to prepare His(trt)-Lys(caprylic)-Phe-Tyr-Ser-Asp-Gln-Gln-Ala-Arg-Phe. The purity and molecular weight of the HKFY-38 are shown in Figs. 101 and 102, respectively. Example 1.39. Preparation of HKFY-39 In order to prepare HKFY-39 ((3S,6S,9S,12S,15S,18S)-3-((2-(((S)-1-(((S)-1-(((S)-1 amino-I-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1 oxopropan-2-yl)amino)-2-oxoethyl)carbamoyl)-18-((S)-2-amino-3-(1-trityl-1H-imidazol-4 yl)propanamido)-6-(3-amino-3-oxopropyl)-15-benzyl-12-(4-hydroxybenzyl)-9 (hydroxymethyl)-5,8,11,14,17,24-hexaoxo-4,7,10,13,16,23-hexaazahentriacontanoic acid), DMF containing 20% piperidine and Fmoc-Gly-OH and HOBt (hydroxyl-benzotriazole) were added to Fmoc-Ala-Arg(pbf)-Phe-trityl resin obtained from Example 1.38. to prepare Fmoc-Gly-Ala-Arg(pbf)-Phe-trityl resin. DMF containing 20% piperidine and Fmoc Asn(trt)-OH and HOBt (hydroxyl-benzotriazole) were added to the Fmoc-Gly-Ala-Arg(pbf) Phe-trityl resin to prepare Fmoc-Asn(trt)-Gly-Ala-Arg(pbf)-Phe-trityl resin. Fmoc-Gln(trt)
OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tbu)-OH, and Fmoc-Phe-OH were sequentially added in the same manner as above to prepare Fmoc-Phe-Tyr(tBu)-Ser(tBu)-Gly-Ala-Arg(pbf)-Phe trityl resin. Fmoc-Lys(caprylic)-OH obtained from Example 1.1. and HOBt (hydroxyl benzotriazole) were added to the resin to prepare Fmoc-Lys(caprylic)-Phe-Tyr(tBu)-Ser(tBu) Gly-Ala-Arg(pbf)-Phe-trityl resin. DMF containing 20% piperidine and Fmoc-His(trt)-OH obtained from Example 1.1. and HOBt (hydroxyl-benzotriazole) were added to the resin to prepare Fmoc-His(trt) Lys(caprylic)-Phe-Tyr(tBu)-Ser(tBu)-Gly-Ala-Arg(pbf)-Phe-trityl resin. The protecting group was cleaved from the Fmoc-His(trt)-Lys(caprylic)-Phe Tyr(tBu)-Ser(tBu)-Gly-Ala-Arg(pbf)-Phe-trity resin, and the resin was then purified to prepare His(trt)-Lys(caprylic)-Phe-Tyr-Ser-Gly-Ala-Arg-Phe. The purity and molecular weight of the HKFY-39 are shown in Figs. 103 and 104, respectively. Example 1.40. Preparation of HKFY-40 DMF containing 20% piperidine and Fmoc-Gln(trt)-OH and HOBt (hydroxyl benzotriazole) were added to the Fmoc-Ala-Arg(pbf)-Phe-trityl resin obtained from Example 1.39. to prepare Fmoc-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin. Fmoc-Gln(trt)-OH, Fmoc-His(trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Phe-OH were sequentially added in the same manner to prepare Fmoc-Phe-Tyr(tBu) Ser(tBu)-His(trt)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin. Fmoc-Lys(caprylic)-OH obtained from Example 1.1. and Fmoc-His(trt)-OH were sequentially added to the resin in the same manner to prepare Fmoc-His(trt)-Lys(caprylic) Phe-Tyr (tBu)-Ser(tBu)-His(trt)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin. The protecting group was cleaved from the Fmoc-His(trt)-Lys(caprylic)-Phe-Tyr (tBu)-Ser(tBu)-His(trt)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trity resin, and the resin was then purified to prepare His(trt)-Lys(caprylic)-Phe-Tyr-Ser-His-Gln-Gln-Ala-Arg-Phe ((S)-2 ((2S,5S,8S,11S,14S)-2-((1H-imidazol-4-yl)methyl)-14-((S)-2-amino-3-(1-trityl-1H-imidazol 4-yl)propanamido)-11-benzyl-8-(4-hydroxybenzyl)-5-(hydroxymethyl)-4,7,10,13,20 pentaoxo-3,6,9,12,19-pentaazaheptacosanamido)-N1-((S)-5-amino-1-(((S)-I-(((S)-I-(((S)-I amino-I-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1 oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)pentanediamide). The purity and molecular weight of the HKFY-40 are shown in Figs. 105 and 106, respectively. Example 1.41. Preparation of HKFY-41 DMF containing 20% piperidine and Fmoc-Gly-OH and HOBt (hydroxyl benzotriazole) were added to the Fmoc-Ala-Arg(pbf)-Phe-trityl resin obtained from Example 1.39. to prepare Fmoc-Gly-Ala-Arg(pbf)-Phe-trityl resin. Fmoc-Asn(trt)-OH, Fmoc-Gln(trt) OH, Fmoc-Tyr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Lys(caprylic)-OH obtained from Example
1.1., and Fmoc-His(trt)-OH were sequentially added to the resin in the same manner to prepare Fmoc-His(trt)-Lys(caprylic)-Phe-Tyr (tBu)-Gln(trt)-Asn(trt)-Gly-Ala-Arg(pbf)-Phe trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic) Phe-Tyr-Gln-Asn-Gly-Ala-Arg-Phe ((3S,6S,9S,12S,15S,18S)-3-((2-(((S)-1-(((S)-1-(((S)-1 amino-I-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1 oxopropan-2-yl)amino)-2-oxoethyl)carbamoyl)-18-((S)-2-amino-3-(1-trityl-1H-imidazol-4 yl)propanamido)-6-(3-amino-3-oxopropyl)-15-benzyl-12-(4-hydroxybenzyl)-9 (hydroxymethyl)-5,8,11,14,17,24-hexaoxo-4,7,10,13,16,23-hexaazahentriacontanoic acid). The purity and molecular weight of the HKFY-41 are shown in Figs. 107 and 108, respectively. Example 1.42. Preparation of HKFY-42 DMF containing 20% piperidine and Fmoc-Gln(trt) and HOBt (hydroxyl benzotriazole) were added to the Fmoc-Ala-Arg(pbf)-Phe-trityl resin obtained from Example 1.39. to prepare Fmoc-Gly-Ala-Arg(pbf)-Phe-trityl resin. Fmoc-Gln(trt)-OH, Fmoc-His(trt) OH, Fmoc-Tyr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Lys(caprylic)-OH obtained from Example 1.1., and Fmoc-His(trt)-OH were sequentially added to the resin in the same manner to prepare Fmoc-His(trt)-Lys(caprylic)-Phe-Tyr(tBu)-His(trt)-Gln(trt)-Gln(trt)-Ala-Arg(pbf) Phe-trityl resin. The protecting group of the resin was cleaved to prepare His(trt) Lys(caprylic)-Phe-Tyr-His-Gln-Gln-Ala-Arg-Phe ((S)-2-((2S,5S,8S,IIS)-2-((1H-imidazol-4 yl)methyl)-11-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-8-benzyl-5-(4 hydroxybenzyl)-4,7,10,17-tetraoxo-3,6,9,16-tetraazatetracosanamido)-N1-((S)-5-amino-I (((S)-i-(((S)--(((S)-1-amino--oxo-3-phenylpropan-2-ylamino)-5-guanidino-1-oxopentan 2-yl)amino)-1-oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)pentanediamide). The purity and molecular weight of the HKFY-42 are shown in Figs. 109 and 110, respectively. Example 1.43. Preparation of HKFY-43 Fmoc-His(trt)-Lys(caprylic)-Phe-Tyr(tBu)-Gln(trt)-Asn(trt)-Gln(trt)-Ala-Arg(pbf) Phe-trityl resin was prepared in the same manner except that Fmoc-Gln(trt)-OH was used instead of Fmoc-Gly-OH among the constituent amino acids of Example 1.41. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic)-Phe-Tyr-Gln-Asn-Gln-Ala Arg-Phe ((S)-N1-((S)-1-(((S)-1-(((S)-i-amino-I-oxo-3-phenylpropan-2-yl)amino)-5 guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)-2-((2S,5S,8S,11S,14S)-2-(2-amino-2 oxoethyl)-14-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-5-(3-amino-3 oxopropyl)-i-benzyl-8-(4-hydroxybenzyl)-4,7,10,13,20-pentaoxo-3,6,9,12,19 pentaazaheptacosanamido)pentanediamide). The purity and molecular weight of the HKFY-43 are shown in Figs. I IIand 112, respectively. Example 1.44. Preparation of HKFY-44
In order to prepare His(trt)-Lys(caprylic)-Phe-Tyr-Trp, Fmoc-Trp(Boc)-OH and DMF were loaded onto the trityl resin to prepare Fmoc-Trp(Boc)-trityl resin. DMF containing 20% piperidine and Fmoc-Tyr(tBu)-OH and HOBt (hydroxyl-benzotriazole) were added to the Fmoc-Trp(Boc)-trityl resin to prepare Fmoc-Tyr(tBu)-Trp(Boc)-trityl resin. Fmoc-Phe-OH, Fmoc-Lys(caprylic)-OH obtained from Example 1.1., and Fmoc-His(trt)-OH were sequentially added to the resin in the same manner to prepare Fmoc-His(trt)-Lys(caprylic) Phe-Tyr (tBu)-Trp(Boc)-trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic)-Phe-Tyr-Trp (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L phenylalanyl-L-tyrosyl-L-tryptophan). The purity and molecular weight of the HKFY-44 are shown in Figs. 113 and 114, respectively. Example 1.45. Preparation of HKFY-45 D-biotin-His(trt)-K(caprylic)-Bip-Tyr(Boc)-trityl resin was prepared in the same manner except that Fmoc-Bip-OH was used instead of Fmoc-Phe-OH during the preparation process of Example 1.2. The protecting group of the resin was cleaved to prepare biotin His(trt)-K(caprylic)-Bip-Tyr (((S)-3-([,1'-biphenyll-4-yl)-2-((S)-6-octanamido-2-((S)-2-(5 ((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3-(1-trityl-1H imidazol-4-yl)propanamido)hexanamido)propanoyl)-L-tyrosine). The purity and molecular weight of the HKFY-45 are shown in Figs. 115 and 116, respectively. Example 1.46. Preparation of HKFY-46 Fmoc-Phe-OH and DMF were loaded onto the Fmoc-Trp(Boc)-trityl resin obtained from Example 1.44. to prepare Fmoc-Trp(Boc)-trityl resin. Fmoc-Lys(caprylic)-OH obtained from Example 1.1., and Fmoc-His(trt)-OH were sequentially added to the resin in the same manner to prepare Fmoc-His(trt)-Lys(caprylic)-Phe-Trp(Boc)-trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic)-Phe-Trp (N6-octanoyl-N2 (Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tryptophan). The purity and molecular weight of the HKFY-46 are shown in Figs. 117 and 118, respectively. Example 1.47. Preparation of HKFY-47 In order to prepare N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-tyrosyl-L phenylalanine, Fmoc-Phe-OH and DMF were loaded onto the trityl resin to prepare Fmoc Phe-trityl resin. Fmoc-Tyr(Boc)-OH, Fmoc-Lys(caprylic)-OH obtained from Example 1.1., and Fmoc-His(trt)-OH were sequentially added to the resin in the same manner to prepare Fmoc-His(trt)-Lys(caprylic)-Tyr(Boc)-Phe-trity resin. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic)-Tyr-Phe (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L lysyl-L-tyrosyl-L-phenylalanine).
The purity and molecular weight of the HKFY-47 are shown in Figs. 119 and 120, respectively. Example 1.48. Preparation of HKFY-48 In order to prepare HKFY-48 (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L tyrosyl-L-tyrosine), Fmoc-Tyr(Boc)-OH and DMF were loaded onto the trityl resin to prepare Fmoc-Tyr(Boc)-trityl resin. Fmoc-Tyr(Boc)-OH, Fmoc-Lys(caprylic)-OH obtained from Example 1.1., and Fmoc-His(trt)-OH were sequentially added to the resin in the same manner to prepare Fmoc-His(trt)-Lys(caprylic)-Tyr(Boc)-Tyr(Boc)-trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic)-Tyr-Tyr (N6-octanoyl-N2-(Nt-trityl L-histidyl)-L-lysyl-L-tyrosyl-L-tyrosine). The purity and molecular weight of the HKFY-48 are shown in Figs. 121 and 122, respectively. Example 1.49. Preparation of HKFY-49 In order to prepare HKFY-49 (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L phenylalanine), Fmoc-Lys(caprylic)-OH obtained from Example 1.1. and Fmoc-His(trt)-OH were sequentially added to the Fmoc-Phe-trityl resin obtained from Example 1.47. in the same manner to prepare Fmoc-His(trt)-Lys(caprylic)-Phe-trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic)-Phe. The purity and molecular weight of the HKFY-49 are shown in Figs. 123 and 124, respectively. Example 1.50. Preparation of HKFY-50 In order to prepare HKFY-50 (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L phenylalanyl-L-serine), Fmoc-Ser(tBu)-OH and DMF were loaded onto the trityl resin to prepare Fmoc-Ser(tBu)-trityl resin. Fmoc-Phe-OH, Fmoc-Lys(caprylic)-OH obtained from Example 1.1., and Fmoc-His(trt)-OH were sequentially added to the resin in the same manner to prepare Fmoc-His(trt)-Lys(caprylic)-Phe-Ser-trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic)-Phe-Ser. The purity and molecular weight of the HKFY-50 are shown in Figs. 125 and 126, respectively. Example 1.51. Preparation of HKFY-51 His(trt)-Lys(caprylic)-Leu-Tyr (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-ysyl-L leucyl-L-tyrosine) was prepared in the same manner except that Fmoc-Leu-OH was used instead of Fmoc-Tyr(Boc)-OH among the constituent amino acids of Example 1.48. The purity and molecular weight of the HKFY-51 are shown in Figs. 127 and 128, respectively. Example 1.52. Preparation of HKFY-52 Fmoc-Asp(tBu)-OH, Fmoc-Tyr(Boc)-OH, Fmoc-Phe-OH, and Fmoc-His(trt)-OH were sequentially added to the Fmoc-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin obtained from Example 1.38. in the same manner to prepare Fmoc-His(trt)-Phe-Tyr(Boc)-Asp(tBu) Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Phe-Tyr-Asp-Gln-Gln-Ala-Arg-Phe ((6S,9S,12S,15S,18S)-1-amino-6 (((S)-1-amino-I-oxo-3-phenylpropan-2-yl)carbamoyl)-18-((S)-2-((S)-2-((S)-2-amino-3-(1 trityl-1H-imidazol-4-yl)propanamido)-3-phenylpropanamido)-3-(4 hydroxyphenyl)propanamido)-12,15-bis(3-amino-3-oxopropyl)-1-imino-9-methyl 8,11,14,17-tetraoxo-2,7,10,13,16-pentaazaicosan-20-oic acid). The purity and molecular weight of the HKFY-52 are shown in Figs. 129 and 130, respectively. Example 1.53. Preparation of HKFY-53 Fmoc-Lys(caprylic)-OH obtained from Example 1.1., Fmoc-Ser(tBu)-OH, Fmoc Gly-OH, and Fmoc-His(trt)-OH were sequentially added to the Fmoc-Phe-Tyr(Boc)-trityl resin obtained from Example 1.47. in the same manner to prepare Fmoc-His(trt)-Gly Ser(tBu)-Lys(caprylic)-Phe-Tyr(Boc)-trity resin. The protecting group of the resin was cleaved to prepare His(trt)-Gly-Ser-Lys(caprylic)-Phe-Tyr (N6-octanoyl-N2-(Nt-trityl-L histidylglycyl-L-seryl)-L-lysyl-L-phenylalanyl-L-tyrosine). The purity and molecular weight of the HKFY-53 are shown in Figs. 131 and 132, respectively. Example 1.54. Preparation of HKFY-54 Fmoc-Lys(caprylic)-OH obtained from Example 1.1. and DMF and HOBt were added to the Fmoc-Phe-Tyr(Boc)-trityl resin obtained from Example 1.47. to prepare Fmoc Lys(caprylic)-Phe-Tyr(Boc)-trity resin. The protecting group of the resin was cleaved to prepare Lys(caprylic)-Phe-Tyr (N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine). The purity and molecular weight of the HKFY-54 are shown in Figs. 133 and 134, respectively. Example 1.55. Preparation of HKFY-55 Fmoc-His(trt)-OH, and Fmoc-Lys(caprylic)-OH obtained from Example 1.1. were sequentially added to the Fmoc-Phe-Tyr(Boc)-trityl resin obtained from Example 1.47. in the same manner to prepare Fmoc-Lys(caprylic)-His(trt)-Phe-Tyr(Boc)-trityl resin. The protecting group of the resin was cleaved to prepare Lys(caprylic)-His(trt)-Phe-Tyr (Na-(N6 octanoyl-L-lysyl)-Nt-trityl-L-histidyl-L-phenylalanyl-L-tyrosine). The purity and molecular weight of the HKFY-55 are shown in Figs. 135 and 136, respectively. Example 1.56. Preparation of HKFY-56 Fmoc-Asp(tBu)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin was prepared in the same manner except that Fmoc-Asp(tBu)-OH was used instead of Fmoc-Ser(tBu)-OH during the preparation process of Example 1.38. DMF containing 2% NH 2NH 2 .H20 was added to Fmoc-Lys(dde)-OH, and dde was removed to prepare Fmoc-Lys-OH. DMF containing caproic acid and HOBt and DIC was added to the Fmoc-Lys-OH to prepare Fmoc Lys(caproic acid)-OH. Fmoc-Lys(caproic)-OH and Fmoc-His(trt)-OH were sequentially added in the same manner to prepare Fmoc-His(trt)-Lys(caproic)-Phe-Tyr(Boc)-Asp(tBu)-Gln(trt)-Gln(trt)-Ala Arg(pbf)-Phe-trityl resin. The protecting group of the resin was cleaved to prepare His(trt) Lys(caproic)-Phe-Tyr-Asp-Gln-Gln-Ala-Arg-Phe ((6S,9S,12S,15S,18S)-1-amino-6-(((S)-1 amino-I-oxo-3-phenylpropan-2-yl)carbamoyl)-18-((S)-2-((S)-2-((S)-2-((S)-2-amino-3-(1 trityl-1H-imidazol-4-yl)propanamido)-6-(non-1-en-2-ylamino)hexanamido)-3 phenylpropanamido)-3-(4-hydroxyphenyl)propanamido)-12,15-bis(3-amino-3-oxopropyl)-1 imino-9-methyl-8,11,14,17-tetraoxo-2,7,10,13,16-pentaazaicosan-20-oic acid). The purity and molecular weight of the HKFY-56 are shown in Figs. 137 and 138, respectively. Example 1.57. Preparation of HKFY-57 His(2-phenyl)-Lys(caprylic)-d-Phe(methyl)-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(2 phenyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L tyrosine) was prepared in the same manner except that Boc-His(2-phenyl)-OH was used instead of Boc-His(benzhydryl)-OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-57 are shown in Figs. 139 and 140, respectively. Example 1.58. Preparation of HKFY-58 His(1-phenyl)-Lys(caprylic)-d-Phe(methyl)-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(1 phenyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L tyrosine) was prepared in the same manner except that Boc-His(1-phenyl)-OH was used instead of Boc-His(benzhydryl)-OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-58 are shown in Figs. 141 and 142, respectively. Example 1.59. Preparation of HKFY-59 His(1,2-diphenyl)-Lys(caprylic)-d-Phe(methyl)-Tyr (((R)-2-((S)-2-((S)-2-amino-3 (1,2-diphenyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p tolyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Boc-His(1,2 diphenyl)-OH was used instead of Boc-His(benzhydryl)-OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-59 are shown in Figs. 143 and 144, respectively. Example 1.60. Preparation of HKFY-60 His(2-(4-tert-butyl)phenyl)-Lys(caprylic)-d-Phe(methyl)-Tyr (((R)-2-((S)-2-((S)-2 amino-3-(2-(4-(tert-butyl)phenyl)-1H-imidazol-4-yl)propanamido)-6 octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Boc-His(2-(4-tert-butyl)phenyl)-OH was used instead of Boc-His(benzhydryl) OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-60 are shown in Figs. 145 and 146, respectively. Example 1.61. Preparation of HKFY-61 His(1-(4-tert-butyl)phenyl)-Lys(caprylic)-d-Phe(methyl)-Tyr (((R)-2-((S)-2-((S)-2 amino-3-(1-(4-(tert-butyl)phenyl)-1H-imidazol-4-yl)propanamido)-6 octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Boc-His(1-(4-tert-butyl)phenyl)-OH was used instead of Boc-His(benzhydryl) OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-61 are shown in Figs. 147 and 148, respectively. Example 1.62. Preparation of HKFY-62 D-His(benzhydryl)-Lys(caprylic)-d-Phe(methyl)-Tyr (((R)-2-((S)-2-((R)-2-amino-3 (1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p tolyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Boc-d His(benzhydryl)-OH was used instead of Boc-His(benzhydryl)-OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-62 are shown in Figs. 149 and 150, respectively. Example 1.63. Preparation of HKFY-63 His(thiophene)-Lys(caprylic)-d-Phe(methyl)-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(2 (thiophen-2-yl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p tolyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Boc His(thiophene)-OH was used instead of Boc-His(benzhydryl)-OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-63 are shown in Figs. 151 and 152, respectively. Example 1.64. Preparation of HKFY-64 His(4-methoxybenzhydryl)-Lys(caprylic)-d-Phe(methyl)-Tyr (((2R)-2-((2S)-2-((2S) 2-amino-3-(1-((4-methoxyphenyl)(phenyl)methyl)-1H-imidazol-4-yl)propanamido)-6 octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Boc-His(4-methoxybenzhydryl)-OH was used instead of Boc-His(benzhydryl) OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-64 are shown in Figs. 153 and 154, respectively. Example 1.65. Preparation of HKFY-65
His(4-hydroxybenzhydryl)-Lys(caprylic)-d-Phe(methyl)-Tyr (((2R)-2-((2S)-2-((2S) 2-amino-3-(1-((4-hydroxyphenyl)(phenyl)methyl)-1H-imidazol-4-yl)propanamido)-6 octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Boc-His(4-hydroxybenzhydryl)-OH was used instead of Boc-His(benzhydryl) OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-65 are shown in Figs. 155 and 156, respectively. Example 1.66. Preparation of HKFY-66 His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr-NH2, (N-((S)-5-((S)-2-amino-3 (1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-(((R)-1-(((S)-1-amino-3-(4 hydroxyphenyl)-1-oxopropan-2-yl)amino)-1-oxo-3-(p-tolyl)propan-2-yl)amino)-6 oxohexyl)octanamide) was prepared in the same manner except that Fmoc-Tyr-wang resin was used instead of the trityl resin among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-66 are shown in Figs. 157 and 158, respectively. Example 1.67. Preparation of HKFY-67 His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3-chloro) ((S)-2-((R)-2-((S)-2 ((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3 (p-tolyl)propanamido)-3-(3-chloro-4-hydroxyphenyl)propanoic acid) was prepared in the same manner except that Fmoc-Tyr(3-chloro) was used instead of Fmoc-Tyr(tBu) among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-67 are shown in Figs. 159 and 160, respectively. Example 1.68. Preparation of HKFY-68 His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3-nitro) ((S)-2-((R)-2-((S)-2 ((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3 (p-tolyl)propanamido)-3-(4-hydroxy-3-nitrophenyl)propanoic acid) was prepared in the same manner except that Fmoc-Tyr(3-nitro) was used instead of Fmoc-Tyr(tBu) among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-68 are shown in Figs. 161 and 162, respectively. Example 1.69. Preparation of HKFY-69 His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3,5-nitro) ((S)-2-((R)-2-((S)-2 ((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3 (p-tolyl)propanamido)-3-(4-hydroxy-3,5-dinitrophenyl)propanoic acid) was prepared in the same manner except that Fmoc-Tyr(3,5-nitro) was used instead of Fmoc-Tyr(tBu) among the constituent amino acids of Example 1.34.
The purity and molecular weight of the HKFY-69 are shown in Figs. 163 and 164, respectively. Example 1.70. Preparation of HKFY-70 His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3-amino) ((S)-2-((R)-2-((S)-2 ((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3 (p-tolyl)propanamido)-3-(3-amino-4-hydroxyphenyl)propanoic acid) was prepared in the same manner except that Fmoc-Tyr(3-amino) was used instead of Fmoc-Tyr(tBu) among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-70 are shown in Figs. 165 and 166, respectively. Example 1.71. Preparation of HKFY-71 His(benzhydryl)-Om(caprylic)-d-Phe(4-methyl)-Tyr (((R)-2-((S)-2-((S)-2-amino-3 (1-benzhydryl-1H-imidazol-4-yl)propanamido)-5-octanamidopentanamido)-3-(p tolyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Fmoc-Orn(dde) was used instead of Fmoc-Lys(dde) among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-71 are shown in Figs. 167 and 168, respectively. Example 1.72. Preparation of HKFY-72 Biotin-His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr (((S)-2-((S)-2-((S)-3-(1 benzhydryl-1H-imidazol-4-yl)-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4 dlimidazol-4-yl)pentanamido)propanamido)-6-octanamidohexanamido)-3-(p tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in the synthesis process of D-biotin of Example 1.2., using His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr-OH of Example 1.34. The purity and molecular weight of the HKFY-72 are shown in Figs. 169 and 170, respectively. Example 1.73. Preparation of HKFY-73 H(trt)Lys(caprylic)-d-3Pal-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol 4-yl)propanamido)-6-octanamidohexanamido)-3-(pyridin-3-yl)propanoyl)-L-tyrosine) was prepared in the same manner except that Fmoc-d-3Pal was used instead of Fmoc-d-Phe-OH among the constituent amino acids of Example 1.12. The purity and molecular weight of the HKFY-73 are shown in Figs. 171 and 172, respectively. Example 1.74. Preparation of HKFY-74 H(trt)Lys(caprylic)-d-2Nal-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol 4-yl)propanamido)-6-octanamidohexanamido)-3-(naphthalen-2-yl)propanoyl)-L-tyrosine) was prepared in the same manner except that Fmoc-d-2Nal was used instead of Fmoc-d-3Pal among the constituent amino acids of Example 1.73.
The purity and molecular weight of the HKFY-74 are shown in Figs. 173 and 174, respectively. Example 1.75. Preparation of HKFY-75 His(tosyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(1 tosyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L tyrosine) was prepared in the same manner except that Boc-His(tosyl)-OH was used instead of Boc-His(benzhydryl)-OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-75 are shown in Figs. 175 and 176, respectively. Example 1.76. Preparation of HKFY-76 His(trityl)-Lys(caprylic)-d-Phe(4-CF3)-Tyr (((R)-2-((S)-2-((S)-2-amino-3-(1-trityl 1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4 (trifluoromethyl)phenyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Fmoc-d-Phe(4-CF3) was used instead of Fmoc-d-3Pal among the constituent amino acids of Example 1.73. The purity and molecular weight of the HKFY-76 are shown in Figs. 177 and 178, respectively. Example 1.77. Preparation of HKFY-77 His(tbm)-Lys(caprylic)-d-Phe(4-CF3)-Tyr (((R)-2-((S)-2-((S)-3-(1-((2'-(1H-tetrazol -yl)-[1,1'-biphenyll-4-yl)methyl)-1H-imidazol-4-yl)-2-aminopropanamido)-6 octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Boc-His(tbm)-OH was used instead of Boc-His(benzhydryl)-OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-77 are shown in Figs. 179 and 180, respectively. Example 1.78. Preparation of HKFY-78 Boc-Trp-Lys(caprylic)-d-Phe(4-methyl)-Tyr (((R)-2-((S)-2-((S)-2-((tert butoxycarbonyl)amino)-3-(1H-indol-3-yl)propanamido)-6-octanamidohexanamido)-3-(p tolyl)propanoyl)-L-tyrosine) was prepared in the same manner except that Boc-Trp-OH was used instead of Boc-His(benzhydryl)-OH among the constituent amino acids of Example 1.34. The purity and molecular weight of the HKFY-78 are shown in Figs. 181 and 182, respectively. Example 1.79. Preparation of HKFY-79 Fmoc-Lys(dde) and DMF (dimethylformamide) were loaded onto the trityl resin to prepare Fmoc-Lys(dde)-trityl resin. Fmoc-Lys(caprylic acid)-trityl resin was prepared in the same manner as in the synthesis process of Example 1.1. Thereafter, Boc-His(benzhdyryl)
OH was used to prepare His(benzhydryl)-Lys(caprylic) (N2-(Nt-benzhydryl-L-histidyl)-N6 octanoyl-L-lysine). The HKFY peptide derivatives prepared by the above preparation method are shown in Table 1 below.
[Table 1] No. Amino acid sequence IUPAC HKFY-1 His(trt)- N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L Lys(caprylic)-Phe-Tyr phenylalanyl-L-tyrosine HKFY-2 Biotin-His(trt)- N6-octanoyl-N2-(Na-(5-((3aS,4S,6aR)-2-oxohexahydro-1H Lys(caprylic)-Phe-Tyr thieno[3,4-d]imidazol-4-yl)pentanoyl)-Nt-trityl-L-histidyl)-L lysyl-L-phenylalanyl-L-tyrosine HKFY-3 His(benzyl)- N2-(Nt-benzyl-L-histidyl)-N6-octanoyl-L-lysyl-L Lys(caprylic)-Phe-Tyr phenylalanyl-L-tyrosine HKFY-4 d-His(trt)- N6-octanoyl-N2-(Nt-trityl-D-histidyl)-L-lysyl-L Lys(caprylic)-Phe-Tyr phenylalanyl-L-tyrosine HKFY-5 His(4-methyltrityl)- N2-(Nt-(diphenyl(p-tolyl)methyl)-L-histidyl)-N6-octanoyl-L Lys(caprylic)-Phe-Tyr lysyl-L-phenylalanyl-L-tyrosine HKFY-6 His(DAMP-3)- N2-((S)-2-amino-3-(1,3-diphenethyl-2,3-dihydro-1H Lys(caprylic)-Phe-Tyr imidazol-4-yl)propanoyl)-N6-octanoyl-L-lysyl-L phenylalanyl-L-tyrosine HKFY-7 His(DAMP-5)- N2-((S)-2-amino-3-(3-(2-cyclohexylethyl)-2,3-dihydro-1H Lys(caprylic)-Phe-Tyr imidazol-4-yl)propanoyl)-N6-octanoyl-L-lysyl-L phenylalanyl-L-tyrosine HKFY-8 His(DAMP-2)- N2-((S)-2-amino-3-(1,3-bis(2-cyclohexylethyl)-2,3-dihydro Lys(caprylic)-Phe-Tyr 1H-imidazol-4-yl)propanoyl)-N6-octanoyl-L-lysyl-L phenylalanyl-L-tyrosine HKFY-9 His(2-phenylethyl)- N6-octanoyl-N2-(Nt-phenethyl-L-histidyl)-L-lysyl-L Lys(caprylic)-Phe-Tyr phenylalanyl-L-tyrosine HKFY- His(2-naphthalen-1- N2-(Nt-(naphthalen-1-ylmethyl)-L-histidyl)-N6-octanoyl-L 10 methyl)- lysyl-L-phenylalanyl-L-tyrosine Lys(caprylic)-Phe-Tyr HKFY- His(2- N2-(Nt-(2-cyclohexylethyl)-L-histidyl)-N6-octanoyl-L-lysyl 11 cyclohexylethyl)- L-phenylalanyl-L-tyrosine Lys(caprylic)-Phe-Tyr HKFY- His(trt)- N6-(non-1-en-2-yl)-N2-(Nt-trityl-L-histidyl)-L-lysyl-D 12 Lys(caprylic)-d-Phe- phenylalanyl-L-tyrosine Tyr
HKFY- His(trt)- ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4 13 Lys(caprylic)-d- yl)propanamido)-6-(non-1-en-2-ylamino)hexanamido)-3-(4 Phe(4-Cl)-Tyr chlorophenyl)propanoyl)-L-tyrosine HKFY- d-His(trt)- ((R)-2-((S)-2-((R)-2-amino-3-(1-trityl-1H-imidazol-4 14 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(4 Phe(4-Cl)-d-Tyr chlorophenyl)propanoyl)-D-tyrosine HKFY- His(trt)- ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4 15 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(4 Phe(4-Cl)-d-Tyr chlorophenyl)propanoyl)-D-tyrosine HKFY- His(trt)-d- ((R)-2-((R)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4 16 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(4 Phe(4-Cl)-Tyr chlorophenyl)propanoyl)-L-tyrosine HKFY- His(3,3- N2-(Nt-(2,2-diphenylethyl)-L-histidyl)-N6-octanoyl-L-lysyl 17 diphpenylethyl)- L-phenylalanyl-L-tyrosine Lys(caprylic)-Phe-Tyr HKFY- His(Fm)- N2-(Nt-(9H-fluoren-9-yl)-L-histidyl)-N6-octanoyl-L-lysyl-L 18 Lys(caprylic)-Phe-Tyr phenylalanyl-L-tyrosine HKFY- His(phenethyl)- N6-octanoyl-N2-(Nt-phenethyl-L-histidyl)-L-lysyl-L 19 Lys(caprylic)-Phe-Tyr phenylalanyl-L-tyrosine HKFY- His(4- N2-(Nt-((4-methoxyphenyl)(phenyl)methyl)-L-histidyl)-N6 20 methoxylbenzhydryl) octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine -Lys(caprylic)-Phe Tyr HKFY- His(4- N2-(Nt-((R)-(4-chlorophenyl)(phenyl)methyl)-L-histidyl)-N6 21 chlorobenzhydryl)- octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine Lys(caprylic)-Phe-Tyr HKFY- His(4- N6-octanoyl-N2-(Nt-((R)-phenyl(p-tolyl)methyl)-L-histidyl) 22 methylbenzhydryl)- L-lysyl-L-phenylalanyl-L-tyrosine Lys(caprylic)-Phe-Tyr HKFY- His(adamatan-1-yl)- N2-(Nt-(adamantan-1-yl)-L-histidyl)-N6-octanoyl-L-lysyl-L 23 Lys(caprylic)-Phe-Tyr phenylalanyl-L-tyrosine HKFY- His(trt)-Lys(capric)- N6-decanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L 24 Phe-Tyr phenylalanyl-L-tyrosine HKFY- His(trt)-Lys(lauric)- N6-dodecanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L 25 Phe-Tyr phenylalanyl-L-tyrosine
HKFY- His(trt)- N6-tetradecanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L 26 Lys(myristic)-Phe- phenylalanyl-L-tyrosine Tyr HKFY- His(trt)- N6-palmitoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L 27 Lys(palmitic)-Phe- phenylalanyl-L-tyrosine Tyr HKFY- His(trt)- ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4 28 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(4 Phe(4-F)-Tyr fluorophenyl)propanoyl)-L-tyrosine HKFY- His(trt)- ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4 29 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(4 Phe(4-Br)-Tyr bromophenyl)propanoyl)-L-tyrosine HKFY- His(trt)- ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4 30 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- d-His(trt)- ((R)-2-((S)-2-((R)-2-amino-3-(1-trityl-1H-imidazol-4 31 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- His(1,3- ((2R)-2-((2S)-2-((2S)-2-amino-3-(1-((2,4 32 difluorobenzhydryl)- difluorophenyl)(phenyl)methyl)-1H-imidazol-4 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- His(benzhydryl)- N2-(Nt-benzhydryl-L-histidyl)-N6-octanoyl-L-lysyl-L 33 Lys(caprylic)-Phe-Tyr phenylalanyl-L-tyrosine HKFY- His(benzhydryl)- ((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4 34 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- His(benzhydryl)- (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H 35 Lys(caprylic)-d- imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)- tolyl)propanamido)-3-(4-(sulfooxy)phenyl)propanoic acid Tyr(SO3H) HKFY- His(benzhydryl)- (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H 36 Lys(caprylic)-d- imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)- tolyl)propanamido)-3-(4-hydroxy-2,6 Tyr(2,6-di-methyl) dimethylphenyl)propanoic acid HKFY- Gly-Ser-His(trt)- N2-(Na-glycyl-L-seryl-Nt-trityl-L-histidyl)-N6-octanoyl-L 37 Lys(caprylic)-Phe-Tyr lysyl-L-phenylalanyl-L-tyrosine
HKFY- His(trt)- (3S,6S,9S,12S,15S)-15-((S)-2-amino-3-(1-trityl-1H-imidazol 38 Lys(caprylic)-Phe- 4-yl)propanamido)-12-benzyl-3-(((6S,9S,12S,15S)-1,18 Tyr-Ser-Asp-Gln- diamino-6-(((S)-1-amino-i-oxo-3-phenylpropan-2 Gln-Ala-Arg-Phe yl)carbamoyl)-12-(3-amino-3-oxopropyl)-1-imino-9-methyl 8,11,14,18-tetraoxo-2,7,10,13-tetraazaoctadecan-15 yl)carbamoyl)-9-(4-hydroxybenzyl)-6-(hydroxymethyl) 5,8,11,14,21-pentaoxo-4,7,10,13,20-pentaazaoctacosanoic acid HKFY- His(trt)- (3S,6S,9S,12S,15S,18S)-3-((2-(((S)-1-(((S)-1-(((S)-1-amino 39 Lys(caprylic)-Phe- 1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan Tyr-Ser-Gln-Asn- 2-yl)amino)-1-oxopropan-2-yl)amino)-2 Gly-Ala-Arg-Phe oxoethyl)carbamoyl)-18-((S)-2-amino-3-(1-trityl-1H imidazol-4-yl)propanamido)-6-(3-amino-3-oxopropyl)-15 benzyl-12-(4-hydroxybenzyl)-9-(hydroxymethyl) 5,8,11,14,17,24-hexaoxo-4,7,10,13,16,23 hexaazahentriacontanoic acid HKFY- His(trt)- (S)-2-((2S,5S,8S,IIS,14S)-2-((1H-imidazol-4-yl)methyl)-14 40 Lys(caprylic)-Phe- ((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-11 Tyr-Ser-His-Gln-Gln- benzyl-8-(4-hydroxybenzyl)-5-(hydroxymethyl)-4,7,10,13,20 Ala-Arg-Phe pentaoxo-3,6,9,12,19-pentaazaheptacosanamido)-N1-((S)-5 amino-I-(((S)-1-(((S)-1-(((S)-1-amino-I-oxo-3-phenylpropan 2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1 oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)pentanediamide HKFY- His(trt)- (3S,6S,9S,12S,15S,18S)-3-((2-(((S)-1-(((S)-1-(((S)-I-amino 41 Lys(caprylic)-Phe- 1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan Tyr-Gln-Asn-Gly- 2-yl)amino)-1-oxopropan-2-yl)amino)-2 Ala-Arg-Phe oxoethyl)carbamoyl)-18-((S)-2-amino-3-(1-trityl-1H imidazol-4-yl)propanamido)-6-(3-amino-3-oxopropyl)-15 benzyl-12-(4-hydroxybenzyl)-9-(hydroxymethyl) 5,8,11,14,17,24-hexaoxo-4,7,10,13,16,23 hexaazahentriacontanoic acid HKFY- His(trt)- (S)-2-((2S,5S,8S,IIS)-2-((1H-imidazol-4-yl)methyl)-11-((S) 42 Lys(caprylic)-Phe- 2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-8-benzyl Tyr-His-Gln-Gln-Ala- 5-(4-hydroxybenzyl)-4,7,10,17-tetraoxo-3,6,9,16 Arg-Phe tetraazatetracosanamido)-N1-((S)-5-amino-1-(((S)-1-(((S)-1 (((S)-I-amino-I-oxo-3-phenylpropan-2-yl)amino)-5 guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2 yl)amino)-1,5-dioxopentan-2-yl)pentanediamide HKFY- His(trt)- (S)-N1-((S)-1-(((S)-1-(((S)-1-amino-i-oxo-3-phenylpropan-2 43 Lys(caprylic)-Phe- yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1 Tyr-Gln-Asn-Gln- oxopropan-2-yl)-2-((2S,5S,8S,11S,14S)-2-(2-amino-2 Ala-Arg-Phe oxoethyl)-14-((S)-2-amino-3-(1-trityl-1H-imidazol-4 yl)propanamido)-5-(3-amino-3-oxopropyl)-11-benzyl-8-(4 hydroxybenzyl)-4,7,10,13,20-pentaoxo-3,6,9,12,19 pentaazaheptacosanamido)pentanediamide HKFY- His(trt)- N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L 44 Lys(caprylic)-Phe- phenylalanyl-L-tyrosyl-L-tryptophan Tyr-Trp HKFY- Biotin-His(trt)- ((S)-3-([1,1'-biphenyl]-4-yl)-2-((S)-6-octanamido-2-((S)-2-(5 45 Lys(caprylic)- ((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4 Ala(biphenyl)-Tyr yl)pentanamido)-3-(1-trityl-1H-imidazol-4 yl)propanamido)hexanamido)propanoyl)-L-tyrosine HKFY- His(trt)- N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L 46 Lys(caprylic)-Phe- phenylalanyl-L-tryptophan Trp HKFY- His(trt)- N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-tyrosyl-L 47 Lys(caprylic)-Tyr-Phe phenylalanine HKFY- His(trt)- N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-tyrosyl-L 48 Lys(caprylic)-Tyr-Tyr tyrosine HKFY- His(trt)- N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L 49 Lys(caprylic)-Phe phenylalanine HKFY- His(trt)- N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L 50 Lys(caprylic)-Phe-Serphenylalanyl-L-serine HKFY- His(trt)- N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-leucyl-L 51 Lys(caprylic)-Leu- tyrosine Tyr HKFY- His(trt)-Phe-Tyr-Asp-(6S,9S,12S,15S,18S)-1-amino-6-(((S)-1-amino-I-oxo-3 52 Gln-Gln-Ala-Arg-Phephenylpropan-2-yl)carbamoyl)-18-((S)-2-((S)-2-((S)-2-amino 3-(1-trityl-1H-imidazol-4-yl)propanamido)-3 phenylpropanamido)-3-(4-hydroxyphenyl)propanamido) 12,15-bis(3-amino-3-oxopropyl)-1-imino-9-methyl 8,11,14,17-tetraoxo-2,7,10,13,16-pentaazaicosan-20-oicacid
HKFY- His(trt)-Gly-Ser- N6-octanoyl-N2-(Nt-trityl-L-histidylglycyl-L-seryl)-L-lysyl 53 Lys(caprylic)-Phe-TyrL-phenylalanyl-L-tyrosine HKFY- Lys(caprylic)-Phe-TyrN6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine 54 HKFY- Lys(caprylic)- Na-(N6-octanoyl-L-lysyl)-Nt-trityl-L-histidyl-L-phenylalanyl 55 His(trt)-Phe-Tyr L-tyrosine HKFY- His(trt)-Lys(caproic)- (6S,9S,12S,15S,18S)-1-amino-6-(((S)-1-amino-I-oxo-3 56 Phe-Tyr-Asp-Gln- phenylpropan-2-yl)carbamoyl)-18-((S)-2-((S)-2-((S)-2-((S)-2 Gln-Ala-Arg-Phe amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-(non-1 en-2-ylamino)hexanamido)-3-phenylpropanamido)-3-(4 hydroxyphenyl)propanamido)-12,15-bis(3-amino-3 oxopropyl)-1-imino-9-methyl-8,11,14,17-tetraoxo 2,7,10,13,16-pentaazaicosan-20-oicacid HKFY- His(2-phenyl)- ((R)-2-((S)-2-((S)-2-amino-3-(2-phenyl-1H-imidazol-4 57 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- His(1-phenyl)- ((R)-2-((S)-2-((S)-2-amino-3-(1-phenyl-1H-imidazol-4 58 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- His(1,2-diphenyl)- ((R)-2-((S)-2-((S)-2-amino-3-(1,2-diphenyl-1H-imidazol-4 59 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- His(2-(4-tert- ((R)-2-((S)-2-((S)-2-amino-3-(2-(4-(tert-butyl)phenyl)-1H 60 butyl)phenyl)- imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p Lys(caprylic)-d- tolyl)propanoyl)-L-tyrosine Phe(4-methyl)-Tyr HKFY- His(1-(4-tert- ((R)-2-((S)-2-((S)-2-amino-3-(1-(4-(tert-butyl)phenyl)-1H 61 butyl)phenyl)- imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p Lys(caprylic)-d- tolyl)propanoyl)-L-tyrosine Phe(4-methyl)-Tyr HKFY- d-His(benzhydryl)- ((R)-2-((S)-2-((R)-2-amino-3-(1-benzhydryl-1H-imidazol-4 62 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- His(thiophene)- ((R)-2-((S)-2-((S)-2-amino-3-(2-(thiophen-2-yl)-1H-imidazol 63 Lys(caprylic)-d- 4-yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine
HKFY- His(4- ((2R)-2-((2S)-2-((2S)-2-amino-3-(1-((4 64 methoxybenzhydryl)- methoxyphenyl)(phenyl)methyl)-1H-imidazol-4 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- His(4- ((2R)-2-((2S)-2-((2S)-2-amino-3-(1-((4 65 hydroxybenzhydryl)- hydroxyphenyl)(phenyl)methyl)-1H-imidazol-4 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- His(benzhydryl)- N-((S)-5-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4 66 Lys(caprylic)-d- yl)propanamido)-6-(((R)-1-(((S)-1-amino-3-(4 Phe(4-methyl)-Tyr- hydroxyphenyl)-1-oxopropan-2-yl)amino)-1-oxo-3-(p NH2 tolyl)propan-2-yl)amino)-6-oxohexyl)octanamide HKFY- His(benzhydryl)- (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H 67 Lys(caprylic)-d- imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr(3- tolyl)propanamido)-3-(3-chloro-4-hydroxyphenyl)propanoic chloro) acid HKFY- His(benzhydryl)- (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H 68 Lys(caprylic)-d- imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr(3- tolyl)propanamido)-3-(4-hydroxy-3-nitrophenyl)propanoic nitro) acid HKFY- His(benzhydryl)- (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H 69 Lys(caprylic)-d- imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)- tolyl)propanamido)-3-(4-hydroxy-3,5 Tyr(3,5-nitro) dinitrophenyl)propanoic acid HKFY- His(benzhydryl)- (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H 70 Lys(caprylic)-d- imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr(3- tolyl)propanamido)-3-(3-amino-4-hydroxyphenyl)propanoic amino) acid HKFY- His(benzhydryl)- ((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4 71 Om(caprylic)-d- yl)propanamido)-5-octanamidopentanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- Biotin- ((S)-2-((S)-2-((S)-3-(1-benzhydryl-1H-imidazol-4-yl)-2-(5 72 His(benzhydryl)- ((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4 Lys(caprylic)-d- yl)pentanamido)propanamido)-6-octanamidohexanamido)-3 Phe(4-methyl)-Tyr (p-tolyl)propanoyl)-L-tyrosine
HKFY- His(trt)- ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4 73 Lys(caprylic)-d-3Pal- yl)propanamido)-6-octanamidohexanamido)-3-(pyridin-3 Tyr yl)propanoyl)-L-tyrosine HKFY- His(trt)- ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4 74 Lys(caprylic)-d-2Nal- yl)propanamido)-6-octanamidohexanamido)-3-(naphthalen-2 Tyr yl)propanoyl)-L-tyrosine HKFY- His(tosyl)- ((R)-2-((S)-2-((S)-2-amino-3-(1-tosyl-1H-imidazol-4 75 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- His(trt)- ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4 76 Lys(caprylic)-d- yl)propanamido)-6-octanamidohexanamido)-3-(4 Phe(4-CF3)-Tyr (trifluoromethyl)phenyl)propanoyl)-L-tyrosine HKFY- His(tbm)- ((R)-2-((S)-2-((S)-3-(1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl] 77 Lys(caprylic)-d- 4-yl)methyl)-1H-imidazol-4-yl)-2-aminopropanamido)-6 Phe(4-CF3)-Tyr octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine HKFY- Boc-Trp- ((R)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(1H 78 Lys(caprylic)-d- indol-3-yl)propanamido)-6-octanamidohexanamido)-3-(p Phe(4-methyl)-Tyr tolyl)propanoyl)-L-tyrosine HKFY- His(benzhydryl)Lys(cN2-(Nt-benzhydryl-L-histidyl)-N6-octanoyl-L-lysine 79 aprylic)
Experimental Example 1. Analysis of HKFY derivatives The HKFY derivatives prepared in Examples 1.1. to 1.79. were analyzed for purity and molecular weight using HPLC and Ion-Mass. The results are shown in Table 2 below, and the HPLC analysis results of the HKFY derivatives are shown in Figs. I to 36, 99, 101, 103,105,107,109,111,113,115,117,119,121, 123,125,127,129,131,133,135,137,139, 141,143,145,147,149,151,153,155,157,159,161,163,165,167,169,171,173,175, 177, 179, 181 and 183, and the Ion-Mass analysis results of the HKFY derivatives are shown in Figs. 37 to 72, 100, 102, 104, 106, 108, 110, 112, 114, 117, 118, 120, 122, 124, 126, 128, 130,132,134,136,138,140,142,144,146,148,150,152,154,156,158,160,162,164, 166,168,170,172,174,176,178,180,182 and 184.
[Table 2] No. Purity(%) Molecular weight HKFY-1 96.1 1000.6 HKFY-2 94.8 1210.5 HKFY-3 93.5 810.1 HKFY-4 92.0 1000.5
HKFY-5 86.4 976.2 HKFY-6 95.2 956.6 HKFY-7 99.2 844.9 HKFY-8 93.4 969.1 HKFY-9 98.7 823.3 HKFY-10 98.5 873.1 HKFY-11 97.5 829.1 HKFY-12 96.3 1001.1 HKFY-13 96.9 1018.9 HKFY-14 96.6 1034.1 HKFY-15 98.3 1034.0 HKFY-16 95.3 1035.3 HKFY-17 98.3 914.5 HKFY-18 98.6 898.2 HKFY-19 98.7 836.4 HKFY-20 94.6 709.9 HKFY-21 98.3 709.5 HKFY-22 94.2 709.6 HKFY-23 69.7 709.8 HKFY-24 93.4 989.6 HKFY-25 95.2 1019.1 HKFY-26 89.1 1045.5 HKFY-27 98.1 1073.6 HKFY-28 96.5 980.6 HKFY-29 96.2 1043.1 HKFY-30 97.0 977.1 HKFY-31 92.9 976.7 HKFY-32 90.4 935.48 HKFY-33 98.1 884.9 HKFY-34 93.6 899.3 HKFY-35 93.9 979.4 HKFY-36 92.6 928.6 HKFY-37 96.9 1128.1 HKFY-38 95.6 1793.9 HKFY-39 95.4 1721.4 HKFY-40 96.1 1815.1
HKFY-41 91.8 1634.7 HKFY-42 87.0 1728.9 HKFY-43 88.5 1705.6 HKFY-44 94.2 1171.3 HKFY-45 93.7 1287.0 HKFY-46 96.7 986.1 HKFY-47 97.4 962.8 HKFY-48 98.0 978.9 HKFY-49 93.3 799.1 HKFY-50 88.9 886.6 HKFY-51 95.1 928.2 HKFY-52 96.6 1452.0 HKFY-53 95.9 1105.2 HKFY-54 98.2 583.3 HKFY-55 99.0 962.7 HKFY-56 95.6 1793.9 HKFY-57 97.6 809.12 HKFY-58 90.3 809.12 HKFY-59 98.5 885.22 HKFY-60 95.6 865.23 HKFY-61 96.1 865.23 HKFY-62 97.1 899.43 HKFY-63 96.6 813.42 HKFY-64 96.4 929.51 HKFY-65 96.5 915.49 HKFY-66 95.2 898 HKFY-67 99.2 932.9 HKFY-68 99.2 944 HKFY-69 99.5 990 HKFY-70 98.5 914.51 HKFY-71 98.6 885.48 HKFY-72 93.2 1126.21 HKFY-73 95.5 963.19 HKFY-74 94.4 1012.36 HKFY-75 93.7 888.09 HKFY-76 96.8 1030.2
HKFY-77 98.2 968.17 HKFY-78 98.9 883.1 HKFY-79 95.2 575.35
Experimental Example 2. Confirmation of binding capacity of HKFY derivatives to GPR39 receptor In order to investigate the binding capacity of the HKFY derivatives prepared in Examples 1.1. to 1.79. above to GPR39, a luciferase assay system was used. The luciferase assay system is a method for confirming the degree of activity of a receptor in a cell through the binding of a ligand to the receptor in the cell. Specifically, the fibroblast cell line CV-1 (1x105 cells/mL, Korea Cell Line Bank) was cultured in a 96 well cell culture plate for 24 hours, and then treated with GPR39 and SRE (serum response element) luciferase inserted into adenovirus at 50 MOI (multiplicity of infection) and 25 MOI virus for 3 hours, respectively, and then cultured for 24 hours. In order to give a fasting process, after 24 hours, the medium was replaced with a serum-free medium and cultured for 16 hours. Thereafter, it was treated with each HKFY and HKFY derivative for 6 hours and cultured, and then the expression level of luciferase, a reporter gene, by activated GPR39 was quantified using a luminometer (Table 3).
[Table 3] No. EC5 o ([M) ECmax (-fold induction over basal) HKFY-1 0.15 0.01 20.51 0.57 HKFY-2 0.14 0.07 15 1.87 HKFY-3 4.13 0.15 9.2 2.58 HKFY-4 0.13 0.07 16.8 1.87 HKFY-5 1.84 0.2 16 1.7 HKFY-6 68.4 1.17 15 2.12 HKFY-7 1.56 0.27 16 2.2 HKFY-8 33.65 1.3 17.3 1.22 HKFY-9 42.7 1.2 21 2.52 HKFY-10 46.5 1.1 14 2.12 HKFY-11 57.8 1.5 22 2.2 HKFY-12 0.035 0.002 20.7 2.3 HKFY-13 0.014 0.002 25.7 2.4 HKFY-14 0.02 0.003 20.9 1.4 HKFY-15 0.098 0.005 24.7 2.6 HKFY-16 0.24 0.02 27.9 3.4 HKFY-17 8.12 0.07 20 0.57
HKFY-18 2.29+0.15 10 1.48 HKFY-19 24.6 2.6 18 1.7 HKFY-20 159 2.3 20.26 2.7 HKFY-21 136 1.27 18.3 2.5 HKFY-22 59.8 2.1 21.3 1.8 HKFY-23 2.6 0.17 15 1.37 HKFY-24 0.24 0.07 7.03 0.57 HKFY-25 0.63 0.07 7.72 0.57 HKFY-26 0.28 0.02 19.82 0.57 HKFY-27 0.56 0.06 20.4 0.57 HKFY-28 0.074 0.004 22.95 2.58 HKFY-29 0.31 0.003 26.8 1.87 HKFY-30 0.008 0.001 23.88 3.04 HKFY-31 0.02 0.003 20.9 2.51 HKFY-32 0.002 0.001 21.5 2.7 HKFY-33 0.15 0.07 20 0.57 HKFY-34 0.007 0.001 22.39 4.59 HKFY-35 0.28 0.07 18.9 0.41 HKFY-36 0.15 0.05 9.9 0.28 HKFY-37 1.84 0.2 16 1.7 HKFY-38 3.5 0.02 16.5 0.02 HKFY-39 0.78 0.02 12.1 0.02 HKFY-40 1.3 0.02 13.4 0.02 HKFY-41 9.55 0.02 12.2 0.02 HKFY-42 1.58 0.02 11.8 0.02 HKFY-43 1.21 0.02 12.1 0.02 HKFY-44 0.37 0.07 20 0.47 HKFY-45 0.14 0.05 21 2.58 HKFY-46 0.26 0.15 20 0.28 HKFY-47 0.3 0.02 13 1.7 HKFY-48 0.33 0.02 14.4 2.7 HKFY-49 0.32 0.02 18.3 1.8 HKFY-50 0.7 0.05 16.2 1.5 HKFY-51 0.12 0.02 14.4 1.9 HKFY-52 56.4 0.02 15.5 2.2 HKFY-53 0.34 0.07 8 2.12
HKFY-54 25.9 0.27 7.8 2.5 HKFY-55 2.49 0.12 16.8 2.5 HKFY-56 0.03 0.002 14.9 1.8 HKFY-57 0.26 0.01 8.5 2.3 HKFY-58 0.02 0.002 9.12 2.1 HKFY-59 0.55 0.02 6.76 2.2 HKFY-60 0.19 0.01 28.2 2.5 HKFY-61 0.02 0.003 9.88 1.8 HKFY-62 0.83 0.03 28.1 2.1 HKFY-63 0.006 0.001 13.5 1.8 HKFY-64 0.007 0.001 16 1.5 HKFY-65 0.003 0.002 18.3 2.2 HKFY-66 0.011 0.001 20.2 3.5 HKFY-67 0.043 0.003 10.2 1.51 HKFY-68 0.013 0.001 10.8 1.41 HKFY-69 0.015 0.002 12.2 2.5 HKFY-70 0.02 0.001 10.1 1.6 HKFY-71 0.012 0.003 16.4 2.51 HKFY-72 0.011 0.002 10.4 1.12 HKFY-73 0.023 0.001 11.6 2.3 HKFY-74 0.008 0.001 18.8 3.2 HKFY-75 0.001 0.002 15.9 4.12 HKFY-76 0.007 0.001 14.2 3.75 HKFY-77 0.007 0.002 11.6 2.14 HKFY-78 0.009 0.001 11.4 1.54 HKFY-79 0.97 0.03 11.2 1.4 As a result, referring to Table 3, it was confirmed that all HKFY derivatives had high activity at nM to M level for GPR39. In addition, among the analogs in which various fatty acids were conjugated to Lys, the analog conjugated to caprylic acid showed the most excellent activity. Derivatives exhibiting an activity at nM level are considered to have highly selective and specific activity for GPR39. On the other hand, HKFY-30, HKFY-34, HKFY-63, HKFY-64, and HKFY-65 derivatives exhibited a higher activity level than other HKFY derivatives. In particular, HKFY-30 and HKFY-34 composed of d-Phe(methyl) exhibited the most excellent activity and high ECmax value. Experimental Example 3. Confirmation of selectivity and specificity of HKFY derivatives for GPR39
In order to confirm the selectivity and specificity of the HKFY derivatives for GPR39, the degree of activity was confirmed by a luciferase assay system and a calcium influx assay system (Fig. 73 and Table 4). Specifically, the luciferase assay system analyzed the degree of activity using HKFY 34 among the HKFY derivatives in Experimental Example 2 above (top in Fig. 73). In the calcium influx assay system, the fibroblast cell line CV-1 (1x105 cells/mL) was transfected with a mixture of human GPR39 (pCDNA3.1_hGPR39, American Type Culture Collection), Gaq (pCDNA3.1_Gaq, American Type Culture Collection), Aequrin (pCDNA3.1_aequrin, American Type Culture Collection) and lipofectamine (American Type Culture Collection). Thereafter, the medium was replaced with a serum-free medium, and after 16 hours of fasting, treated with HKFY-34 for 6 hours and cultured. After culturing, the degree of binding of calcium activated by activated GPR39 to aequrin was quantified using a luminometer (bottom in Fig. 73).
[Table 4] Item Reporter gene assay Ca2+ influx assay EC5 o (nM) ECmax (-fold EC5 o (nM) ECmax (-fold induction over induction over basal) basal) HKFY-34 6.7 0.7 22.39 4.59 2.7 0.5 2.4 4.59 HKFY N.D
As a result, referring to Fig. 73 and Table 4, it was confirmed that when treated with HKFY-34, the binding capacity and activity to the GPR39 receptor were excellent. In addition, through the activity test of the HKFY derivatives for similar receptors to GPR39, ghrelin receptor family (ghrelin receptor (GHSR), motilin receptor (MTLR), neurotensin receptor (NTSR1 & NTSR2), neuromedin U receptor (NMU1 & NMU2), TRH (thyrotropin releasing hormone) receptor (TRHR)), the selectivity and specificity for the GPR39 receptor were confirmed. Specifically, the degree of activity between the intrinsic ligand and HKFY-34 for each receptor was analyzed using a luciferase assay system (Fig. 74). As a result, referring to Fig. 74, it was confirmed that the activity of HKFY-34 for GHSR, MTLR, NTSR1 & NTSR2, NMU1 & NMU2 and TRHR was very low. These results suggest that the HKFY derivative can be used as an agonist that selectively and specifically binds to the GPR39 receptor. Experimental Example 4. Evaluation of promoting activity of HKFY-34 on intestinal tissue cell growth It is known from studies using GPR39 deficient mice that GPR39 is involved in the growth and differentiation of intestinal tissue cells (Phil. Trans. R. Soc. B., 2016,
371:20150420). Therefore, in order to confirm the effect of HKFY-34 on the growth of intestinal tissue cells, the degree of cell proliferation by HKFY-34 was measured using HT-29 cells (Korea Cell Line Bank), which are intestinal epithelial cells. Specifically, HT-29 cells were cultured in a 96 well plate and then treated with HKFY-34 at different concentrations for 24, 48, and 72 hours. The cell proliferation of the cultured cells was measured using a Cellvia kit (AB frontier) and a BrdU cell proliferation kit (abeam). As a result, the proliferation of HT-29 cells was increased by HKFY-34 in a dose dependent manner (Fig. 75). It is known from studies using GPR39 deficient mice that calcium signaling is involved in the growth of intestinal tissue cells by GPR39 (Phil. Trans. R. Soc. B. 2016, 371:20150420). Therefore, it was confirmed whether calcium signaling is involved in the cell growth promoted by HKFY-34. Specifically, HT-29 cells were cultured in a 96-well black culture plate and then treated with HKFY-34, and the calcium ion concentration in the cells was measured using a Fluo-8 directTM calcium assay kit (Thermo Fisher Scientific). As a result, the calcium ion concentration in HT-29 cells was increased by HKFY-34 compared to the untreated group (vehicle) (Fig. 76). Experimental Example 5. Evaluation of promoting activity of HKFY-34 on tight junction It is known that GPR39 is involved in the protection of the gastrointestinal tract (Phil. Trans. R. Soc. B., 2016, 371:20150420). Therefore, in order to confirm the effect of HKFY-34 on the gastrointestinal tract protective function by GPR39, the promoting activity of HKFY-34 on tight junction was evaluated using HT-29 cells, which are important for intestinal tissue formation. Specifically, the HT-29 cells were treated with HKFY-34 at different concentrations, and then the expression levels of mRNA (Fig. 77) and protein (Fig. 78) of ZO-1 and occludin, which are important factors of tight junction in intestinal barrier function, were confirmed through quantitative RT-PCR (qPCR) and Western blot. As a result, the expression levels of mRNA and protein of ZO-1 and occludin were significantly increased by HKFY-34 in a dose dependent manner compared to the untreated group (vehicle) (Fig. 77 and Fig. 78). It is known that tight junctions are mediated by a signaling mechanism due to phosphorylation of AMPK protein. Therefore, in order to confirm whether AMPK is involved in the increase in tight junctions by HKFY-34, the expression of p-AMPK in the cells was confirmed using HT-29 cells (Figs. 79 and 80). As a result, the expression of the p-AMPK protein was increased by HKFY-34 in a dose-dependent manner compared to the untreated group (vehicle) (Fig. 79). In addition, when treated with HKFY-34 after pretreatment with an AMPK inhibitor (STO-609), it was confirmed that the expression level of p-AMPK, which was increased due to HKFY-34 treatment, was decreased (Fig. 80). These results indicate that HKFY-34 acts as a GPR39 agonist, thereby enhancing tight junction. Experimental Example 6. Evaluation of anti-inflammatory activity of HKFY-34 in cell model of inflammatory bowel disease In order to confirm the effect of HKFY-34 on anti-inflammatory action, which is one of the gastrointestinal tract protective function (barrier function) by GPR39, the anti inflammatory activity of HKFY-34 was evaluated in a cell model of inflammatory bowel disease (IBD). Specifically, the HT-29 cells were treated with 1 g/mL LPS to induce inflammation and prepare an inflammatory bowel disease model, and were treated with HKFY-34 at different concentrations. Thereafter, the expression levels of mRNA (Fig. 81) and protein (Fig. 82) of inflammation factors for ulcerative colitis were measured through qPCR and ELISA. As a result, the mRNA expression levels of IL-8, IL-6, IL- Iand TNF-a, which are pro-inflammatory cytokines increased by LPS treatment, were significantly decreased by HKFY-34 treatment in a dose-dependent manner (Fig. 81). In addition, the secretion levels of IL-8, IL-6, IL- Iand TNF-a in HT-29 cells treated with LPS were also significantly decreased by HKFY-34 treatment in a dose-dependent manner (Fig. 82). These results indicate that HKFY-34, which acts as a GPR39 agonist, may have an effect of alleviating and treating inflammation in inflammatory bowel disease. Experimental Example 7. Evaluation of anti-inflammatory activity of HKFY-34 in animal model of inflammatory bowel disease The anti-inflammatory activity of HKFY-34 in an animal model of inflammatory bowel disease was evaluated. Specifically, an animal model of ulcerative colitis among inflammatory bowel diseases was prepared by feeding C57BL6/J mice (Central Lab. Animal Inc.) with water containing 3% DSS (dextran sodium sulfate). The untreated (vehicle) mice were set as a control group, the mice fed with only DSS (vehicle+3% DSS) were set as a negative control group, and the mice administered intraperitoneally with SASP (sulfasalazine) at 50 mg/kg after treatment with DSS (SASP 50 mg/kg+3% DSS) were set as a positive control group. As a test group, the mice were intraperitoneally administered with HKFY-34 at 0.1, 1, and 10 mg/kg, respectively. HKFY-34 was administered once a day for 5 days, and during the administration period, the stool condition and body weight loss were measured in the subjects. Stool condition was observed for the degree of stool softness (stool consistency, diarrhea) and the degree of blood in stool (fecal bleeding), and a score was assigned from the lowest 0 to the highest 3 in proportion to the severity compared to the control group.
As a result, body weight loss, a symptom of ulcerative colitis, was significantly inhibited by HKFY-34 in a dose-dependent manner in the test group administered with HKFY-34 compared to the positive control group, SASP (Fig. 83). In addition, as a result of measuring the length of the colon of all subjects who completed the administration, the length contraction of the colon due to inflammatory damage was reduced by HKFY-34 in a dose dependent manner in the HKFY-34 test group compared to the negative control group (Fig. 84). As a result of observing the stool in each subject, it was also confirmed that ulcerative colitis was alleviated in a dose-dependent manner in the test group administered with HKFY-34 (Figs. 85 and 86). In order to confirm the anti-inflammatory action of HKFY-34 administration on colon tissue, the mRNA expression levels of pro-inflammatory cytokines in colon tissue for each group were confirmed by qPCR. As a result, the mRNA expression levels of IL-8, IL-6, IL- IPand TNF-a in the intestinal tissue were significantly decreased in the group administered with HKFY-34 compared to the negative control group (Fig. 87). In addition, the concentrations of IL- IPand TNF-a in the blood were significantly decreased in the HKFY-34 test group compared to the negative control group (Fig. 88). For histological analysis of the colon tissues of each group, H&E (hematoxylin and eosin) staining was performed on the colon tissues of the negative control group, the positive control group, and the test group. For the stained tissue, the infiltration rate of immune cells (macrophages) in the colonic mucosa, the loss rate of mucus secreting cells, the structural collapse rate of colonic villi, and the loss rate of secretory glands were confirmed, and the degree of damage was analyzed by comparing it with the control group to assign a score. As a result, it was confirmed that the degree of damage caused by inflammation of the colon tissue was alleviated in the test group administered with HKFY-34 compared to the negative control group (Fig. 89). In addition, as a result of confirming the expression levels of important factors for tight junction of the colon tissue in each subject, the mRNA expression levels of ZO-1 and occludin were significantly increased by HKFY-34 in a dose-dependent manner in the subject treated with HKFY-34 (Fig. 90). Experimental Example 8. Evaluation of anti-inflammatory activity of HKFY-34 in inflammatory bowel disease-induced GPR39 deficient mouse model In order to confirm the effect of HKFY-34 in an inflammatory bowel disease model using GPR39 as a target substance, a disease model of ulcerative colitis was prepared using GPR39 deficient mice (GPR39 knock out (KO), Gpr39-/-). At this time, wild type mice born from a litter were set as a control group for each treated group of GPR39 deficient mice. Specifically, an animal model of ulcerative colitis was prepared by feeding GPR39 deficient mice (Lexicon pharmaceuticals) and wild type mice with water containing 3% DSS in the same manner as in Experimental Example 7. GPR39 KO mice fed with only DSS (vehicle+3% DSS) were set as a negative control group, and GPR39 KO mice administered with HKFY-34 (10 mg/kg) (HKFY-34 10 mg/kg+3% DSS) were set as a test group. Intraperitoneal administration was performed once a day for 5 days. As a result, body weight loss was inhibited by administration of HKFY-34 in ulcerative colitis-induced wild type mice. On the other hand, no inhibitory effect of HKFY-34 on body weight loss was observed in the ulcerative colitis-induced GPR39 deficient mice (Fig. 91). In addition, the decrease in colon length was inhibited by administration of HKFY-34 in the ulcerative colitis-induced wild type mice. On the other hand, the inhibitory effect of HKFY-34 on the reduction of colon length was not observed in the ulcerative colitis-induced GPR39 deficient mice (Fig. 92). As a result of observing the stool conditions of individual GPR39 deficient mice in which ulcerative colitis was induced, the effect of alleviating stool consistency and blood in stool was not observed in the test group administered with HKFY-34 compared to the negative control group (Figs. 93 and 94). As a result of analyzing histological morphology through H&E (hematoxylin and eosin) staining, it was observed that, in ulcerative colitis-induced wild type mice, damage due to inflammation of colon tissue was reduced in the test group administered with HKFY-34. On the other hand, in ulcerative colitis-induced GPR39 deficient mice, the effect of HKFY-34 reducing inflammatory damage was not observed (Fig. 95). These results indicate that HKFY-34 did not mitigate ulcerative colitis in GPR39 deficient mice, indicating that HKFY-34 is an agonist targeting GPR39.
Claims (1)
- Claims[Claim 1] A compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof:[Formula 1] R3NA H 0 0 H H Rj N N N N R1 H O (CH2 )n H 0 RHNR R R4 0 in Formula 1 A is -C(-Ro)-, -N= or -N(-R1)-, Cy is C6- 14 aryl or 5 to 6-membered heteroaryl, R 1 and R3 are each independently hydrogen, Ra, an amine protecting group, C 1-6 alkyl substituted with 1 to 3 Ra, C3-10 cycloalkyl, or 5 to 6-membered heterocyclyl, wherein said heterocyclyl has or does not have 1 to 3 substituents selected from phenylethyl and cyclohexylethyl, R2 is hydrogen, Ra, or 5 to 6-membered heterocyclyl, and Ro is hydrogen, or Ro and R2 are linked to each other to form a benzene ring together with the two carbon atoms to which they are attached, Ra is each independently C 3 - 10 cycloalkyl or C6- 14 aryl, wherein said aryl has or does not have one or more substituents selected from the group consisting of halogen, -OH, C 6 - 14 aryl substituted with 5 to 6-membered heteroaryl, C1-6 alkyl and C1 -6alkoxy, n is I to 10, R 4 is hydrogen, Ci-io alkyl or C-C2 alkylcarbonyl, R 5 is hydrogen, halogen, CF3 or C1 -6alkyl, R6 is hydrogen, Ci-io alkyl or -S(=0) 20H, R7 and Rs are each independently hydrogen, halogen, nitro, amine or C1 -6alkyl, R9 is -OH or -NH 2, and Rio is hydrogen, an amine protecting group or biotin, wherein said heterocyclyl and heteroaryl each independently contain at least one heteroatom selected from the group consisting of N, S and 0.[Claim 2]The compound or pharmaceutically acceptable salt thereof according to claim 1, whereinR 1 is hydrogen, or[Claim 3] The compound or pharmaceutically acceptable salt thereof according to claim 1, whereinR2 is hydrogen, or R2 is hydrogen, Ra, or 5 to 6-membered heterocyclyl, and Ro is hydrogen, or Ro and R2 are linked to each other to form a benzene ring together with the two carbon atoms to which they are attached.[Claim 4] The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R3 is one selected from the group consisting ofIand[Claim 5] The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein A is -C(-Ro)- or -N=.[Claim 6] The compound or pharmaceutically acceptable salt thereof according to claim 1, whereinR3 is .[Claim 7] The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein n is 3 or 4, and R4 is heptylcarbonyl.[Claim 8] The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R5 is methyl or CF 3 .[Claim 9] The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R6 is hydrogen or S(=0) 2 0H.[Claim 10] The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R7 and R8 are each independently hydrogen or amine.[Claim 11] The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R9 is -OH.[Claim 12] The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Rio is hydrogen, p-toluenesulfonyl (Ts), t-butoxycarbonyl (Boc) or biotin.[Claim 13]The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein said Cy is pyridyl, naphthyl or phenyl.[Claim 14] The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is any one selected from the group consisting of: 1) His(trt)-Lys(caprylic)-Phe-Tyr, 2) Biotin-His(trt)-Lys(caprylic)-Phe-Tyr, 3) His(benzyl)-Lys(caprylic)-Phe-Tyr, 4) d-His(trt)-Lys(caprylic)-Phe-Tyr, 5) His(4-methyltrityl)-Lys(caprylic)-Phe-Tyr, 6) His(DAMP-3)-Lys(caprylic)-Phe-Tyr, 7) His(DAMP-5)-Lys(caprylic)-Phe-Tyr, 8) His(DAMP-2)-Lys(caprylic)-Phe-Tyr, 9) His(2-phenylethyl)-Lys(caprylic)-Phe-Tyr, 10) His(2-naphthalen-1-methyl)-Lys(caprylic)-Phe-Tyr, 11) His(2-cyclohexylethyl)-Lys(caprylic)-Phe-Tyr, 12) His(trt)-Lys(caprylic)-d-Phe-Tyr, 13) His(trt)-Lys(caprylic)-d-Phe(4-Cl)-Tyr, 14) d-His(trt)-Lys(caprylic)-d-Phe(4-Cl)-d-Tyr, 15) His(trt)-Lys(caprylic)-d-Phe(4-Cl)-d-Tyr, 16) His(trt)-d-Lys(caprylic)-d-Phe(4-Cl)-Tyr, 17) His(3,3-diphenylethyl)-Lys(caprylic)-Phe-Tyr, 18) His(Fm)-Lys(caprylic)-Phe-Tyr, 19) His(phenethyl)-Lys(caprylic)-Phe-Tyr, 20) His(4-methoxylbenzhydryl)-Lys(caprylic)-Phe-Tyr, 21) His(4-chlorobenzhydryl)-Lys(caprylic)-Phe-Tyr, 22) His(4-methylbenzhydryl)-Lys(caprylic)-Phe-Tyr, 23) His(adamantan-1-yl)-Lys(caprylic)-Phe-Tyr, 24) His(trt)-Lys(capric)-Phe-Tyr, 25) His(trt)-Lys(lauric)-Phe-Tyr, 26) His(trt)-Lys(myristic)-Phe-Tyr, 27) His(trt)-Lys(palmitic)-Phe-Tyr, 28) His(trt)-Lys(caprylic)-d-Phe(F)-Tyr, 29) His(trt)-Lys(caprylic)-d-Phe(Br)-Tyr, 30) His(trt)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 31) d-His(trt)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 32) His(1,3-difluorobenzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr,33) His(benzhydryl)-Lys(caprylic)-Phe-Tyr, 34) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 35) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(SO3H), 36) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(2,6-di-methyl), 57) His(2-phenyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 58) His(1-phenyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 59) His(1,2-diphenyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 60) His(2-(4-tert-butyl)phenyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 61) His(1-(4-tert-butyl)phenyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 62) d-His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 63) His(thiophene)-Lys(caprylic)-d-Phe(4-methyl)-Tyr, 64) His(4-methoxybenzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr 65) His(4-hydroxybenzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr 66) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr-NH2 67) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3-chloro) 68) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3-nitro) 69) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3,5-nitro) 70) His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr(3-amino) 71) His(benzhydryl)-Orn(caprylic)-d-Phe(4-methyl)-Tyr 72) Biotin-His(benzhydryl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr 73) His(trt)-Lys(caprylic)-d-3Pal-Tyr 74) His(trt)-Lys(caprylic)-d-2Nal-Tyr 75) His(tosyl)-Lys(caprylic)-d-Phe(4-methyl)-Tyr 76) His(trt)-Lys(caprylic)-d-Phe(4-CF3)-Tyr 77) His(tbm)-Lys(caprylic)-d-Phe(4-CF3)-Tyr 78) Boc-Trp-Lys(caprylic)-d-Phe(4-methyl)-Tyr.[Claim 15] The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein two amino acids or derivatives thereof are further bound to the N terminus of the compound represented by Formula 1.[Claim 16] The compound or pharmaceutically acceptable salt thereof according to claim 15, wherein the compound is (Xi)-(X 2)-[His(trt)-Lys(caprylic)-Phe-Tyr], wherein Xi and X 2 are each independently any one amino acid selected from 20 amino acids or derivatives thereof.[Claim 17] The compound or pharmaceutically acceptable salt thereof according to claim 16, wherein the compound is 37) Gly-Ser-His(trt)-Lys(caprylic)-Phe-Tyr.[Claim 18] The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein 1 to 10 amino acids or derivatives thereof are further bound to the C terminus of the compound represented by Formula 1.[Claim 19] The compound or pharmaceutically acceptable salt thereof according to claim 18, wherein the compound is [His(trt)-Lys(caprylic)-Phe-Tyr]-(X3)a-(X4)-(X)c-(X6)d-(X7)e-(X8)f (X9)g, wherein X 3 to X 9 are each independently any one amino acid selected from 20 amino acids or derivatives thereof, and a to g are 0 or 1, and at least one of them is 1.[Claim 20] The compound or pharmaceutically acceptable salt thereof according to claim 19, wherein the compound is any one selected from the group consisting of: 38) His(trt)-Lys(caprylic)-Phe-Tyr-Ser-Asp-Gln-Gln-Ala-Arg-Phe, 39) His(trt)-Lys(caprylic)-Phe-Tyr-Ser-Gln-Asn-Gly-Ala-Arg-Phe, 40) His(trt)-Lys(caprylic)-Phe-Tyr-Ser-His-Gln-Gln-Ala-Arg-Phe, 41) His(trt)-Lys(caprylic)-Phe-Tyr-Gln-Asn-Gly-Ala-Arg-Phe, 42) His(trt)-Lys(caprylic)-Phe-Tyr-His-Gln-Gln-Ala-Arg-Phe, 43) His(trt)-Lys(caprylic)-Phe-Tyr-Gln-Asn-Gln-Ala-Arg-Phe, and 44) His(trt)-Lys(caprylic)-Phe-Tyr-Trp.[Claim 21] A compound or a pharmaceutically acceptable salt thereof, wherein the compound consists of [His(trt)-Lys(caprylic)]-(Xio)h-(X1)i, wherein Xio and Xii are each independently any one amino acid selected from 20 amino acids or derivatives thereof, and h and i are 0 or 1, and at least one of them is 1.[Claim 22] The compound or pharmaceutically acceptable salt thereof according to claim 21, wherein the compound is any one selected from the group consisting of: 45) Biotin-His(trt)-Lys(caprylic)- Ala(biphenyl)-Tyr, 46) His(trt)-Lys(caprylic)-Phe-Trp, 47) His(trt)-Lys(caprylic)-Tyr-Phe, 48) His(trt)-Lys(caprylic)-Tyr-Tyr, 49) His(trt)-Lys(caprylic)-Phe, 50) His(trt)-Lys(caprylic)-Phe-Ser, and 51) His(trt)-Lys(caprylic)-Leu-Tyr.[Claim 23] A compound or a pharmaceutically acceptable salt thereof, wherein the compound is any one selected from the group consisting of: 52) His(trt)-Phe-Tyr-Asp-Gln-Gln-Ala-Arg-Phe, 53) His(trt)-Gly-Ser-Lys(caprylic)-Phe-Tyr, 54) Lys(caprylic)-Phe-Tyr, 55) Lys(caprylic)-His(trt)-Phe-Tyr 56) His(trt)-Lys(caproic)-Phe-Tyr-Asp-Gln-Gln-Ala-Arg-Phe, and 79) His(benzhydryl)Lys(caprylic).[Claim 24] A pharmaceutical composition for preventing or treating inflammatory bowel disease, comprising the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 as an active ingredient.[Claim 25] A health functional food composition for preventing or mitigating inflammatory bowel disease, comprising the compound or cytologically acceptable salt thereof according to any one of claims 1 to 23 as an active ingredient.[Claim 26] A method for preventing or treating inflammatory bowel disease, comprising administering the compound or pharmaceutically acceptable salt thereof according to any one of claims I to 23 to a mammal.[Claim 27]Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, for the manufacture of a medicament for preventing or treating inflammatory bowel disease.[51] 20 21 A (230nm) 0.5 0.5RP-P-28-2 RP-P-28-2 10 ug0.4 0.40.3 0.3Vols0.2 0.20.1 0.12330 21-4320.0 0.00 & 10 15 20 25 30 35(Minutes)(230nm) A Pk # M2H PIX % 1 23,350 63523 1.98927,450 27816 0.871 2 3 29.667 3068947 96.115 34,492 32718 1.025 4(Totals) 3193004 100,000( 191) ISA/KR[52]1.4 1.41.2 1.21.0 1.00.8 0.806 080.4 0.40.2 0.20.0 0.00 5 10 15 20 25 30 35(Minutes)A (230nm) NIZH Pk # I 11,100 197288 % 1.523 2 16,983 17888 0.138 3 18,392 196860 1.519 4 18.567 12283334 94.800 5 18.900 78709 0.607 6 19,458 47579 0.367 7 20.075 17696 0.137 8 21,175 117722 0.909(Totals) 12957076 100.000191) ISA/KR[53] 280130.5 A (230nm) 05RP-P 61 RP-P-61 10 ug0.4 0.40.3 0.3Vols Vote0.2 020.1 010.0 0.010 15 20 25 30 35 0 $(Minutes)A (230nm) Pk # NZH PIX I 24.042 154621 4.070 2 27.742 75873 1,9973 28.075 3554888 93.5814 28.300 13353 0.352(Totals) 100.000 3798735ISA/KR[54](230nm)RP-P-62 0.30 0.30 RP-P-62 10 193 35%! 0.26 0.250.20 0.200.15 0.150.10 0.10228080.08 18842 0.05 223800.00 0.005 10 15 20 25 30 35 0 (Minutes)(230nm) Pk # NIK! I 11.025 62109 2,934% 2 12,950 20881 0.9873 16.842 36403 1,7204 18,142 3561 0.1685 18.283 1948911 92.0786 18.500 1995 0.0947 22.908 42723 2.018(Totals) 2116583 100.000191) ISA/KR[55]1.4 1,41.2 121.0 1.00.8 080.6 0.60.4 0.40.2 0.30.0 0.0-0.2 -0.2S 10 15 20 25 30 35 0(Minutes)A (230nm) Pk # DIXI PIX % I 7,567 543240 3.648 14.250 320281 2,151 2 3 14.900 121055 0.813 16.808 174902 1,175 4 5 16,983 12877998 86.4816 17.567 3349 0.0227 22.675 850376 5,711(Totals) 14891201 100,000191) ISA/KR(66] 1.2 1.21.0 1.00.8 0.80.6 3.8as 040.2 0.20.0 0.0ES 0 10 15 20 25 30 35({Minutes)A (230nm) DIGO AIRI Pk # } 18,583 106135 % 0.771 2 18.875 160971 1.169 3 19.175 6898 0.050 4 19,575 19104 0.139 5 20,550 301263 2.188 6 20,733 13111960 95,248 7 21,100 59808 0.434(Totals) 13766139 100,000191) ISA/KR[57] 0.9 0.90.8 0.80.7 0.70.6 0.60.5 0.50.4 0.40.3 0.30.2 0.20.1 08991 20393 0.1200.0 0.00.1 0.1a 5 10 15 20 25 30 35y (Minutes)DONA (230um) Pk # MRI DIX DIX % I 18.400 5826 0.074 2 18.858 35246 0.447 3 19.242 7829715 99,2844 19,650 9412 0,119 5 20.933 5988 0.076(Totals) 7886187 100,000ISA/KR[58]0.8 0.9 AR2!0.8 0.80.7 0.70.8 0.0U.S 0.90.4 0.40.3 0.30.2 0.20.1 0.10.0 0.0-0.1 -2.80 § 10 16 20 25 30 35(Minutes)(230mm) A MRI DIXI Pk # I 9.908 66138 % 1.165 2 10.967 87970 1.550 3 17,900 5302869 93.429 4 18,408 13019 0.229 5 19,433 49635 0.875 6 19.808 156170 2,752(Totals) 5675801 100,000191) ISA/KR[59] 0.8 0.6AIR0.5 050.4 0.40.3 0.30.2 0.20 3 0.10.0 0.00 3 10 15 20 25 30 35 (Minutes)(230nm) A Pk # MRI OIX DIXI % 1 11,442 12941 0.312 2 15,925 5875 0.142 3 16.383 4092136 98.762 4 16,950 20590 0.497 5 17.183 11904 0.287(Totals) 4143446 100,000() 191) ISA/KR[510]0.7 0.7NRH0.6 0.60.5 050.4 0.40.3 0.30.2 0.20.1 0.1180.0 0.00 3 18 16 20 25 30 38A (230nm) Pk # pix } 17.725 18123 % 0.4202 17,833 4250624 98,538 3 17,983 30335 0.703 4 19.608 14588 0.338Totals 4313670 100.000(ii 191) ISA/KR[E11] 0.6 0.511210.5 0.50.4 040.3 0.30.2 0.20.1 0.10.0 0.015 20 25 30 35 0 5 10 (Minutes)(230nm) A Pk # } 121 17.392 10683 % 0.2602 17,892 32920 0.8023 18,050 4004850 97.5804 18.208 55703 1.357(Totals) 4104156 100.000( 191) ISA/KR[512]ASMA (230nm) 8P-P 161 0.8 0.8 PP-P-161 5 09 35%III 196 A1230.7 0.70.8 0.80.5 0.50.4 0.40.3 0.30.2 0.20.1 0.1 $3830.0 0.0-0.1 0.15 10 15 20 25 30 S5 C you (Minutes)A (230nm) Pk il DISE MIH OIL 01 % I 8.325 59060 0.6602 14.550 7368 0.0823 14.892 13809 0.1544 15.275 8623400 96.3665 15,725 179390 2.0056 16,242 20819 0.2337 22.050 44743 0.500(Totals) 8948589 100.000191) ISA/KR[513] A (230nm) 14 14 RP-P-35 RP-P-35 10ug 35%12 1210 1408 08Votte06 osor on0.2 2004 or00 00$ 16 15 20 28 30 33 II. (Minutes)A (230nm) Pk # I 10.125 273095 1.0852 14.292 78126 0.310 3 15,433 198667 0.789 4 16.133 102854 0.409 5 16.317 24397418 96.920 6 22.075 122505 0.487ON (Totals) 25172665 100.000() 191) ISA/KR[514] 8.4 1.4- (230nm) RP-P-171 RP-P-171 10 ug 35% 1.2 1.81.0 1.00.8 08Vols Votte0.0 as0.8 as0.2 0.0 02/203.3 0810 15 20 20 39 36 a 5 It: (Minutes)A (230nm) Pk # I2 3 de$ 9.017 16.017 16.308 16,458 16.850 419285 186695 19243 19094399 352969 % 2,056 0.915 0.094 93,622 1.7316 17.217 98631 0.4847 21,283 224010 1.098OH (Totals) 20395232 100.000ISA/KR(E15]A (230nm)0.8 RP-P-171 as RP-P-171 60 ug 35%3.3 0.7see 080.8 0.5Vots Vots 0.4 as93 as0.2 330.8 a: 35580.0 as-0.301 $4 to 15 20 25 30 35 @ FLI (Minutes)(230nm) Pk # I2 3 4 5 9.592 16.192 16.317 17.133 21.692 57605 25089 7933977 13676 40346 %0.714 0.311 98.306 0.169 0.500JHI (Totals) 8070693 100.000191) ISA/KR[516]10 10x2 080.8 VolsVote sa04 as#2 0208 and30 38 $ 10 IS 20 20 & (Minutes)(230nm) PL # DE PAY 16.142 239822 2.224 1 23,250 83633 0.776 2 95,369 3 23,383 10282106 23,850 65708 0.609 4 1.021 5 27.817 110077(Totals) 100.000 10781346ISA/KR[517]++++++++ 287 A (230mm) RP-P-105 0.8 as RP-P-105 20% 10 ugDES N2 07 0708 0.80.5 0.6Vote Vote 0.4 as0.3 030.2 02as 0*0.0 as#3 WS S 10 15 28 30 as(Minutes) x2871 A (230nm) Ph # ma I 19,300 24967 0.350 2 19,800 68572 0.960 3 19.908 7023210 98,320 4 20,142 26477 0.371Bell (Totals) 7143226 100,000(/ 191) ISA/KR[518] 2871 A (230nm) 19 08 RP-P-106 OF RP-P-106 20% 10 ug DIES N2 0.7 as@@ @#0.8 asWots Vote the ofa.x 0.30.2 020.5 2008 01 8 : 8 0.0 as0.8 $ 1$ is 28 30 as - FR (Minutes) a287 A (230nm) Ph # 95% I 18,100 13747 0.2312 18.950 19141 0.658 ) 19.058 5870147 98,675 19,267 19618 0.330 4 20,042 6304 0.106 $AND (Totals) 5948959 100.000191) ISA/KR[519] (230nm) RP-P-169 07 or RP-P-159 5ug 35%OF 0000 0504 04Votte Votteas as0.2 02# $ C.I00 004* $ 19 15 20 29 30 a # (Minutes)(230nm) Pk # I2 3 15,475 15.608 15,883 50688 6175342 25274 % 0.811 98.785 0.404OH (Total) 6251304 100.000ISA/KR[520]00N2! is 18of **08 08 Vote Vote0.4 $40.8 0.20.8 as15 20 28 30 a $ * * (Minutes)as 71 A (230nm) DISE NICH DE 3% Pk # I 14,767 289107 1.5272 15,342 180802 0.9553 15.500 17916634 94,624 16.017 390814 2,064 4 $ 16.833 34476 0.1826 17,233 3383 0.0187 17,492 17 0.000 27.658 119373 0.630 $B (Totals) 18934606 100,0001)1 ISA/KR[521]38.9 227 A (230nm) as RP-P-147 RP-P-147,5 ug or 0.8 MINI0.7 07as 060.$ 0.5 VoteVoteSt 0.40.8 0302 020.8 01so 0.00.0 01 " $ 10 18 20 25 30 38FB (Minutes)4871 A (230nm) CI Ph # DI I 28.742 88777 0.715 2 28,858 12210973 98.300 3 29,200 122457 0.986(Totals) 12422207 100.000491)ISA/KR[522]* $ 10 MADE08 0808 08Vote VoteS.A 0.402 as0.0 @@$8 to 18 388 30% $ 20 30(Minutes)227A (230nm) Pk # PR I 19.725 205133 1.507 2 30,258 317097 2,329 3 30.733 118786 0.872 30,875 12833064 94,255 4 $ 31,267 123991 0.911 6 32,192 13547 0.099 7 32,633 3687 0.027is (Totals) 13615307 100,000ISA/KR[523]1344(230nm) 3.0 RP-P-136 RP-P-136 50 ug 35%38.8 0.808 @@Votie Votieas 84$12.000.2 3.2300130.0 080 $ $8 18 20 25 30 30FIE (Minutes)A (230nm) Pk #% 2.226 I 9.983 419168 2 13,308 98863 0.525 3 13.842 13141015 69.7864 14.042 4227269 22.449 5 14.475 910387 4.835 6 15.508 33724 0.179ON (Totals) 18830426 100.00001 ISA/KR[524]us - 8.21.00.8 asVide Vete the as3.4 040.2 or DAY0.0 as$ * 18 18 20 28 AN # & (Minutes)2871A (230mm) may (3) P% # I 13,467 190642 1,561 2 15,567 $407 0.069 $ 19,233 221053 1,810 $ 19,508 11414199 93,475 $ 20,000 200540 1.716 6 22,858 167161 1.369(Totals) 12211004 100,000191) ISA/KRE25] as 0.80.4 0.40.3 0.3Vote Vote0.2 0.20.8 01 23 080.0 as$ $ 10 15 20 25 30 36FL (Minutes)(230nm) Pk #% I 16.858 1.945 60541 2 21.925 34729 1.116 3 22.375 2964448 95.244 4 22.850 18248 0.586 5 23,683 34505 1.109OH (Totals) 3112471 100.000[526]A (230nm) 247RP-P-35-3 as - RP-P-35-3 10ug 35% 650.4 Rdas 03 Votsas 0.230-442.88 0.1 0.12321as 0.0$ $ 18 15 20 25 30 35(Minutes)(230nm) Pk #% you 17.908 348504 7.6202 21.258 63048 1,379 3 21,767 4075184 89.1034 25,958 48137 1,053 $ 30.142 38702 0.846ONL (Totals) 4573575 100.000ISA/KR[527]8679(230nm)0.35 - RP-P 35-4 RP-P-35-4 10ug 35% 0.350.88 0.300.23 0.25Volts saw 0.20 Volte0.33 2.150.18 an 20.500.00 0.000.00 0.000 $ 10 16 20 28 35 FL (Minutes) $(230nm) Pk # I 1% 20.350 48563 1.841 2 24.758 2589232 98.159OHN (Totals) 2637795 100.000191) ISA/KR[528] 2014$8.8 www 287 A (230nm) 0.5 1311RP-P 17-6 RP-P-176 10ug 25%Q.$ as0.3 0.3VoteVotie0.2 02as 012018$ 0.0 0.0$ 10 18 20 28 30 38 a (Minutes)227 A or 31% (230nm) M2I an Pk # & 14,508 51960 1,250 18.708 3827 0.092 3 20,167 53447 1,262 3 20,408 8234 0.198 4 5 20.575 4013472 96,560 6 26.650 26509 0.638BY (Totals) 4156449 100.000191) ISA/KR[529] 1.4 0.8 2412287 A (230nm) RP-P1771.2 - RP-P-177 10ug 25% $.21.0 8.80.8 0.8Votie Volia06 asas 240.2 02 and200.0 0018 20 28 38 S $ - * (Minutes)287 A (230nm) PER 98% Ph # I 15.617 368222 1,961 20.608 105656 0.563 2 21,217 74954 0.399 $ 21,517 18067630 96.215 $ 0.286 $ 21,908 53777 26.625 108110 0.576 6BAG (Totals) 18778349 100.000191) ISA/KR[530] 2008227 A (230nm)0.0 - RP-P 178 RP-P-178 10ug 25% 080.8 as&* 0.4Wote Vote 0.3 and02 02$ $ as and 3 8 12 2 A. 0.0as29 30 as 10 18 $ x (Minutes) RP-P-178(230nm) Ph # 94% 93938 1,596 I 15,000 20.642 13182 0.224 2 1395 0.024 20.842 $ 5712933 97.071 21,008 $ 0.331 21,783 19455 $ 0.754 26,633 44381 6BE (Totals) 100,000 5885284191) ISA/KR[531]1.2 1.21.0 100.8 0808 060.4 as02 22-12 02 300* as asse 10 15 28 25 30 as 5 (Minutes)(230nm) Pk # 4% I 10.233 464967 2.640 17,917 67529 0.383 3 3 18.058 16374452 92.957 18.558 384999 2.186 4 5 19,392 2352 0.013 22,167 320866 1.822 6ON (Totals) 17615165 100.000491 ISA/KR
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| KR1020210120647A KR20230037391A (en) | 2021-09-09 | 2021-09-09 | Composition for preventing or treating inflammatory bowl disease comprising novel compound |
| KR10-2021-0120647 | 2021-09-09 | ||
| PCT/KR2022/013535 WO2023038464A1 (en) | 2021-09-09 | 2022-09-08 | Composition for preventing or treating inflammatory bowel disease containing novel compound |
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| JP (1) | JP2024517582A (en) |
| KR (1) | KR20230037391A (en) |
| CN (1) | CN117616034A (en) |
| AU (1) | AU2022342994A1 (en) |
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| US20040005664A1 (en) * | 2000-04-25 | 2004-01-08 | Millennium Pharmaceuticals, Inc. | Novel 26199, 33530, 33949, 47148, 50226, 58764, 62113, 32144, 32235, 23565, 13305, 14911, 86216, 25206 and 8843 molecules and uses therefor |
| AR080592A1 (en) * | 2010-03-26 | 2012-04-18 | Lilly Co Eli | PEPTIDE WITH ACTIVITY FOR GIP-R AND GLP-1-R, FAMILY FORMULATION THAT UNDERSTANDS IT, ITS USE TO PREPARE A USEFUL MEDICINAL PRODUCT FOR THE TREATMENT OF MELLITUS DIABETES AND TO INDICATE WEIGHT LOSS |
| GB201101459D0 (en) * | 2011-01-27 | 2011-03-16 | Imp Innovations Ltd | Novel compounds and thier effects on fedding behaviour |
| EP2773366B1 (en) * | 2011-11-04 | 2017-03-01 | Lipotec, S.A. | Peptides which inhibit activated receptors and their use in cosmetic or pharmaceutical compositions |
| TWI669309B (en) * | 2015-06-22 | 2019-08-21 | 美商美國禮來大藥廠 | Glucagon and glp-1 co-agonist compounds |
| WO2021182898A1 (en) * | 2020-03-11 | 2021-09-16 | 애니젠 주식회사 | Composition for anti-diabetes and anti-obesity comprising novel compound |
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